Sham Irradiation Research Articles

Innovative 1064-nm Nd:YAG Laser Significantly Improves Keratosis Pilaris, A Randomized, Double-Blind, Sham-Irradiation-Controlled Trial.

Keratosis pilaris (KP) isa commonfollicular disorder for which various topical agents and energy-based devices have been used with some efficacy. To evaluate the efficacy of a novel 1064-nm Nd:YAG laser for the reduction of skin roughness, erythema, and hyperpigmentation in KP subjects. Twenty-three subjects with untreated KP on the upper outer arms participated in a randomized, single-blind fashion. One arm of each subject was divided into upper and lower parts. One part was randomized to be treated with an innovative 1064-nm Nd:YAG laser, while the other part received sham irradiation. Subjects received four consecutive treatments at 4-week intervals. Antera3D was used to measure skin roughness, erythema, and hyperpigmentation at baseline and 4 weeks after the last treatment. Moreover, clinical outcomes were also evaluated by subjects' Global Improvement Score (GIS) and subjects' satisfaction grading scores. Twenty-three subjects completed the study. There was statistically significant reduction of skin roughness measured by Antera3D compared with control group (P < 0.001). There were statistically significant improvements of skin roughness, erythema, hyperpigmentation, and overall appearances graded by subjects' Global Improvement Score (P < 0.001 all). Subjects' satisfaction scores were graded significantly better in treatment parts (P < 0.001). No adverse events including burning, bulla, erosion, post-inflammatory hyper/hypopigmentation, and scar formation developed in any subjects throughout the study period. This innovative 1064-nm Nd:YAG laser has proved to significantly and safely reduce skin roughness in Thai KP subjects compared with control after four sessions. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

The effects of androgen deprivation therapy and radiation therapy on cancer-related fatigue.

10 Background: Fatigue is a common symptom characterized by incapacitating tiredness. Androgen deprivation therapy (ADT) in combination with radiotherapy (RT) is one of the standard treatments for prostate cancer. Fatigue often worsens during RT with concomitant ADT and it persists long after treatment completion. The purpose of this study is to examine the effects of combined ADT and RT on fatigue in prostate cancer men and in a fatigue mouse model. Methods: 64 participants were recruited and followed at baseline, midpoint, completion, and 1 year post-RT. Two cohorts of men: +ADT cotinued after RT (n=27), +ADT during RT only (n=20), and -ADT (n=17). Fatigue was measured using FACT-F. Male C57BI/6 mice (n=55) were randomly placed into 2 groups: +ADT and –ADT (control). Mice were further subdivided into +RT and –RT (sham) groups. Voluntary Wheel Running Activity (VWRA) data from all mice were recorded for 6 days post-irradiation and the total average of all 6 days was used for analysis. Results: Fatigue (n=64) worsened during RT ( p=.02 at midpoint, p=.04 at completion). ADT significantly affected fatigue development over time (F3,42 = 3.80, p=.02) with the most significant difference occurring at midpoint ( p&lt;.001) and completion of RT ( p&lt;0.001). VWRA significantly decreased in mice that received the combination of ADT and irradiation, compared to those that received only ADT + sham radiation ( p=.001) and no ADT + sham radiation ( p=.004). Transcription factor A, mitochondrial (TFAM) in brain cortical samples was significantly reduced in irradiated mice compared to control mice ( p=.014). Glucose transported type 4 (GLUT4) in brain cortices was significantly reduced in irradiated mice compared to non-irradiated mice ( p=.0057). GLUT4 was also significantly reduced in irradiated mice receiving ADT compared to control mice receiving sham RT ( p=.043). Conclusions: There is a significant combined effect of ADT and RT on fatigue in both humans and mice. Mitochondrial function/neuronal bioenergetic markers were altered in the cortices of irradiated mice that received concomitant ADT. These findings suggest that fatigue experienced by subjects who receive ADT + RT could be attributable to impaired cortical energy production.

P2.03-34 Fractalkine Attenuate Irradiation-Induced Brain Injury Through Promoting the M2 Polarization of Microglia

Radiation-induced brain injury (RIBI) is an unavoidable adverse side-effect induced by cranial radiation therapy. The neuro-inflammation mediated by activated microglia has been proved to be a key role in RIBI by our previous researches. Studies have demonstrated that vascular endothelial cells are damaged by irradiation and Fractalkine (FKN), a crucial mediator modulating the biological activity of microglia, is released. However, the role of FKN in RIBI was poorly understood. The aim of this study was to investigate the effect of FKN on RIBI and its underlying mechanisms. Human Umbilical Vein Endothelial Cells (HUVEC) was subjected to 10 Gy or sham irradiation, FKN expression was detected by Western blotting (WB), qRT-PCR and ELISA, γH2AX formation and nuclear translocation of p65 was analyzed by immunocytochemistry (ICC). BV-2 cells received 10-Gy irradiation after being cultured for 3 h with or without FKN (100ng/ml), or co-cultured with HUVEC. Moreover, the CX3CR1 (the receptor of FKN on microglia) wide-type (CX3CR1WT) and CX3CR1-knockdown (CX3CR1-/-) mice were employed and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector 3 days before 10-Gy whole brain irradiation. The polarization of microglia in vitro or in hippocampus and its inflammatory factors release were evaluated through measuring the signature genes, protein and cytokines of M1/M2 phenotype by RT-PCR, WB and ELISA at different time-points after irradiation. Hippocampus neurogenesis was evaluated through detecting the proliferation marker BrdU/nestin and differentiation marker BrdU/NeuN by immunofluorescence (IF) respectively. Neurological function was evaluated by morris water maze (MWM) at 6 weeks after RIBI, and the relationship between microglia and vascular was explored by IF. Then the in vitro phagocytosis assays were performed to investigate if FKN could promote BV2’ phagocytic function. The expression of FKN in HUVEC was increased by 10 Gy irradiation, simultaneously, γH2AX formation and p65 nuclear translocation were observed. FKN regardless from exogenous or secreted by HUVEC could promote the M2 polarization of microglia and inhibit inflammatory response in vitro， it also enhanced neurogenesis in hippocampus, and improved function recovery in CX3CR1WT mice, but not in CX3CR1-/-mice after RIBI. More interestingly, activated microglia migrated to blood vessels in CX3CR1WT mice was observed in vivo by IF. What’s more, BV2 cells phagocytized more fluorescent microspheres when treated with FKN. The FKN/CX3CR1 axis plays an important role in RIBI, and might be an underlying target for the treatment of radiation-induced cognitive impairment.

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [18F]HX4 PET imaging study in colorectal cancer xenografts

BackgroundIn a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [18F]flortanidazole ([18F]HX4) small-animal positron emission tomography (μPET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [18F]HX4 as a predictive and/or prognostic biomarker within this setup.MethodsColo205-bearing mice (n = 40) underwent a baseline [18F]HX4 hypoxia μPET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [18F]HX4 was administered intravenously 30 min later, whereupon a second μPET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were further divided into four therapy groups (n = 10/group): control (1), metformin (2), radiotherapy (3), and metformin + radiotherapy, i.e., combination (4). Then, they received a second dose of metformin (groups 2 and 4) or saline (groups 1 and 3), followed by a single radiotherapy dose of 15 Gy (groups 3 and 4) or sham irradiation (groups 1 and 2) 30 min later. Tumor growth was followed three times a week by caliper measurements to assess the therapeutic outcome.Results[18F]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [18F]HX4 tumor-to-background ratio (TBR) from 2.53 ± 0.30 to 2.28 ± 0.26 (p = 0.04), as opposed to saline treatment (2.56 ± 0.39 to 3.08 ± 0.39; p = 0.2). The median tumor doubling time (TDT) was 6, 8, 41, and 43 days in the control, metformin, radiotherapy and combination group, respectively (log-rank p < 0.0001), but no metformin-specific therapy effects could be detected. Baseline [18F]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02).ConclusionsMetformin decreased [18F]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [18F]HX4 holds promise as a prognostic imaging biomarker.

BIO 300, a Nanosuspension of Genistein, Mitigates Radiation-Induced Erectile Dysfunction and Sensitizes Human Prostate Cancer Xenografts to Radiation Therapy

To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity. Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy. Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay. BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT.

Monocyte Polarization is Altered by Total-Body Irradiation in Male Rhesus Macaques: Implications for Delayed Effects of Acute Radiation Exposure.

Radiation-induced fibrosis (RIF) is a common delayed effect of acute ionizing radiation exposure (DEARE) affecting diverse tissues including the heart, lungs, liver and skin, leading to reduced tissue function and increased morbidity. Monocytes, which may be classified into classical (CD14++, CD16-), intermediate (CD14++, CD16+) and non-classical (CD14+/low, CD16++) subtypes in humans and non-human primates (NHPs), and monocyte-derived macrophages may play an integral role in the pathogenesis of RIF. We tested the hypothesis that moderate to high levels of total-body exposure to radiation would alter monocyte polarization and produce phenotypes that could promote multi-organ fibrosis in a wellestablished NHP model of DEARE. Subjects were 16 young adult male rhesus macaques, ten of which were exposed to high-energy, 4 Gy X-ray total-body irradiation (TBI) and six that received sham irradiation (control). Total monocytes assessed by complete blood counts were 89% depleted in TBI animals by day 9 postirradiation (P < 0.05), but recovered by day 30 postirradiation and did not differ from control levels thereafter. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) and sorted into classical, intermediate and non-classical subsets using fluorescence-activated cell sorting (FACS) prior to and at 6 months post-TBI. At 6 months postirradiation, monocyte polarization shifted towards lower classical (92% → 86%) and higher intermediate (7% → 12%) and non-classical monocyte subsets (0.6% → 2%) (all P < 0.05) in TBI animals compared to baseline. No change in monocyte subsets was observed in control animals. Transcriptional profiles in classical and intermediate monocyte subsets were assessed using RNAseq. Classical monocyte gene expression did not change significantly over time or differ cross-sectionally between TBI and control groups. In contrast, significant numbers of differentially expressed genes (DEGs) were detected in intermediate monocyte comparisons between the TBI animals and all animals at baseline (304 DEGs), and in the TBI versus control animals at 6 months postirradiation (67 DEGs). Intermediate monocytes also differed between baseline and 6 months in control animals (147 DEGs). Pathway analysis was used to identify genes within significant canonical pathways, yielding 52 DEGs that were specific to irradiated intermediate monocytes. These DEGs and significant canonical pathways were associated with pro-fibrotic and anti-inflammatory signaling pathways that have been noted to induce M2 macrophage polarization. These findings support the hypothesis that TBI may alter monocyte programming and polarization towards a profibrotic phenotype, providing a novel target opportunity for therapies to inhibit or prevent RIF.

DMAPT is an Effective Radioprotector from Long-Term Radiation-Induced Damage to Normal Mouse Tissues In Vivo.

While radiotherapy is widely used in cancer treatment, the benefits can be limited by radiation-induced damage to neighboring healthy tissues. We previously demonstrated in mice that the anti-inflammatory compound dimethylaminoparthenolide (DMAPT) selectively induces radiosensitivity in prostate tumor tissue from transgenic adenocarcinoma of mouse prostate (TRAMP) mice, while simultaneously protecting healthy tissues from 6 Gy whole-body radiation-induced apoptosis. Here, we examined the radioprotective effect of DMAPT on fibrosis in normal tissues after a partial-body fractionated radiation protocol that more closely mimics the image-guided fractionated radiotherapy protocols used clinically. Male C57BL/6J mice, 16 weeks old, received 20 Gy fractionated doses of X rays (2 Gy daily fractions, five days/week for two weeks) or sham irradiation to the lower abdomen, with or without a prior 20 mGy dose to mimic an image dose. In addition, mice received thrice weekly DMAPT (100 mg/kg by oral gavage) or vehicle control from 15 weeks of age until time of analysis at 6 weeks postirradiation. In the absence of exposure to radiation, there were no significant differences observed in the tissues of DMAPT and vehicle-treated mice (P > 0.05). DMAPT treatment significantly reduced radiation-induced testis weight loss by 60.9% (P < 0.0001), protected against a decrease in the seminiferous tubule diameter by 42.1% (P < 0.0001) and largely preserved testis morphology. Inclusion of the image dose had no significant effect on testis mass, seminiferous tubule diameter or testis morphology. DMAPT reduced radiation-induced fibrosis in the corpus cavernous region of the penis (98.1% reduction, P = 0.009) and in the muscle layer around the bladder (80.1% reduction, P = 0.0001). There was also a trend towards reduced collagen infiltration into the submucosal and muscle layers in the rectum. These results suggest that DMAPT could be useful in providing protection from the radiation-induced side effects of impotence and infertility, urinary incontinence and fecal urgency resulting from prostate cancer radiotherapy. DMAPT is a very well-tolerated drug and can conveniently be delivered orally without strict time windows relative to radiation exposure. Protection of normal tissues by DMAPT could potentially be useful in radiotherapy of other cancer types as well.

Feasibility study of blood oxygen level-dependent magnetic resonance imaging in evaluating the response of metastatic lymph nodes of rabbit VX2 tumor to radiotherapy

Objective: To investigate the feasibility of blood oxygen level-dependent magnetic resonance imaging (MRI) in evaluating the response of metastatic lymph nodes of rabbit VX2 tumor to radiotherapy. Methods: Twenty-eight healthy New Zealand white rabbits which were provided by the Laboratory Animal Center of Soochow University, male or female, 2 to 3 months, weighing 2 to 3 kg, were used to establish the animal model of VX2 tumor popliteal fossa metastatic lymph node, and then were divided into either the radiotherapy group (n=16) or the control group (n=12). The radiotherapy group received a 20 Gy radiotherapy per rabbit, the control group received sham radiotherapy. All rabbits underwent MRI scan on four time points, including before (0 day), 3rd, 7th and 14th days after radiotherapy. The two parameters of size and R(2*) value (s(-1)) of lymph node were measured. At each time point,two rabbits in each group were sacrificed randomly to resect lymph nodes for pathological examination, and two parameters of microvessel density (MVD, strip/HP) and apoptosis index (AI, %) were analyzed. The parameters among the four time points in each group or between the two groups were compared. The correlation of lymph node size and R(2*) value with MVD or AI was analyzed, respectively. Results: A significant size difference was neither between the two groups or among the each time points in each group (P>0.05). The R(2*) of lymph node in the radiotherapy group was (29.6±1.7),(36.8±2.6),(44.8±5.8) and (57.7±6.2) s(-1) at the time points of 0, 3, 7 and 14 days, respectively, showing a gradual increase trend; MVD was (52.3±2.5),(41.0±3.6),(34.0±3.6) and (22.7±2.5) strip/HP respectively, showing a decreasing trend; AI was 12.8%±0.5%,14.9%±0.6%,20.6%±0.5% and 27.5%±0.7% respectively, showing a gradual increase trend (all P<0.05). In the control group, both R(2*) value and AI among the four time points did not change statistically (all P>0.05), but MVD showed a gradual increase trend,(50.0±3.0),(53.0±1.7),(60.3±2.5) and (70.0±2.0) strip/HP, respectively, P<0.05. There were significant differences in R(2*) and MVD at 3, 7 and 14 days, in AI at 7 and 14 days between the two groups (all P<0.05). There was a linear correlation of R(2*) value, but not of size, with MVD and AI (r=-0.87 and 0.94, respectively). Conclusion: Blood oxygen level-dependent MRI can indirectly reflect the hypoxic status of metastatic lymph nodes after radiotherapy, and has potential value in evaluating the response of metastatic lymph nodes to radiotherapy.

Astrocytes-derived VEGF exacerbates the microvascular damage of late delayed RBI

Overexpression of vascular endothelial growth factor (VEGF) is considered the most critical factor in radiation-induced brain injury (RBI). To investigate the role of VEGF and the mechanism underlying microvascular damage in RBI, wild type mice, and transgenic mice overexpressing VEGF derived from astrocytes, were separately and randomly exposed to whole-brain or sham irradiation. Pathophysiologic changes in the brain tissue were detected 90 days after irradiation. Compared with wild type mice, the secretion of VEGF and angiopoietin-2 (Ang-2) was up-regulated in transgenic mice, whether irradiated or not, while elevated expression of VEGF, Ang-2, and glial fibrillary acidic protein (GFAP) was detected after whole-brain irradiation using western blotting. Impairment of the blood–brain barrier (BBB) was demonstrated by the leakage of dyes observed using two-photon imaging and decreased expression of zonula occludens-1 (ZO-1) and Occludin. Hematoxylin–eosin (HE) staining revealed obvious structural damage in the irradiated brains. Furthermore, damage to the BBB and histopathology in the transgenic mice were worse than those of wild type mice in the irradiated groups. There was a positive correlation among VEGF and Ang-2 expression and RBI severity. These data reveal that VEGF and Ang-2 expression is closely associated with the microvascular injury in RBI. Further, overexpression of VEGF can cause up-regulation of Ang-2 and exacerbation of RBI. Therefore, Ang-2 might be the cytokine that acts as a mediator between VEGF and microvascular injury, and is likely a new intervention target for RBI.

Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice.

The radiation environment in deep space includes the galactic cosmic radiation with different proportions of all naturally occurring ions from protons to uranium. Most experimental animal studies for assessing the biological effects of charged particles have involved acute dose delivery for single ions and/or fractionated exposure protocols. Here, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice 2 months following rapidly delivered, sequential irradiation with protons (1 GeV, 60%), 16O (250 MeV/n, 20%), and 28Si (263 MeV/n, 20%) at 0, 25, 50, or 200 cGy at 4–6 months of age. Cortical BDNF, CD68, and MAP-2 levels were analyzed 3 months after irradiation or sham irradiation. During the dark period, male mice irradiated with 50 cGy showed higher activity levels in the home cage than sham-irradiated mice. Mice irradiated with 50 cGy also showed increased depressive behavior in the forced swim test. When cognitive performance was assessed, sham-irradiated mice of both sexes and mice irradiated with 25 cGy showed normal responses to object recognition and novel object exploration. However, object recognition was impaired in female and male mice irradiated with 50 or 200 cGy. For cortical levels of the neurotrophic factor BDNF and the marker of microglial activation CD68, there were sex × radiation interactions. In females, but not males, there were increased CD68 levels following irradiation. In males, but not females, there were reduced BDNF levels following irradiation. A significant positive correlation between BDNF and CD68 levels was observed, suggesting a role for activated microglia in the alterations in BDNF levels. Finally, sequential beam irradiation impacted the diversity and composition of the gut microbiome. These included dose-dependent impacts and alterations to the relative abundance of several gut genera, such as Butyricicoccus and Lachnospiraceae. Thus, exposure to rapidly delivered sequential proton, 16O ion, and 28Si ion irradiation significantly affects behavioral and cognitive performance, cortical levels of CD68 and BDNF in a sex-dependent fashion, and the gut microbiome.

Interventions for infantile haemangiomas of the skin

Interventions for infantile haemangiomas of the skin

3173 A Mouse Model to Study Image-Guided, Radiation-Induced Cardiac Injury and Potential Clinically Targetable Biologic Mediators

OBJECTIVES/SPECIFIC AIMS: The overall objective of this study is to develop a novel, clinically-relevant, image-guided mouse model for radiation-induced cardiotoxicity, which can be used to gain insight into clinically-targetable, pathophysiologic mechanisms of cardiac injury in thoracic radiotherapy patients. METHODS/STUDY POPULATION: Photon or sham radiation will be administered at differential doses to a defined portion of the heart and/or lungs of C57BL/6 female mice using micro-CT visualization of the heart with Xstrahl’s MuriSlice Software applied to the Small Animal Radiation Research Platform (SARRP). Cardiac and lung segments from a subset of mice will be harvested at specific time points for confirmation of radiation targeting, local apoptosis assessment, and evaluation of fibrosis and vascular tissue morphology. Quantitative echocardiography, myocardial 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT), and myocardial perfusion imaging (MPI) with Technicium-99 (Tc-99) sestamibi will be implemented to identify sensitive imaging measures of cardiac injury and asses myocardial mechanics, inflammation, and perfusion deficits, respectively. Concurrently, a multiparametric analysis will be conducted to identify novel, circulating biomarkers of cardiotoxicity. RESULTS/ANTICIPATED RESULTS: We hypothesize that a clinically-relevant mouse model can be generated by the in situ, focal irradiation of a portion of heart and/or lung tissue segments, and can be used to elucidate molecular mechanisms of radiation-induced cardiac damage. We anticipate time-dependent and dose-dependent, focal histopathologic changes in the mouse heart, with cardiac fibrosis development, vascular damage, and cellular apoptosis in irradiated mice. Additionally, we anticipate that our mouse model of focal heart irradiation will reveal radiologic and biochemical changes that can be used to characterize and predict radiation-induced cardiac injury. Specifically, we expect our quantitative echocardiography, FDG-PET, and MPI parameters to identify and characterize cardiac damage that topographically matches histopathological analysis, and expect levels of select biochemical markers to differentially vary with time. DISCUSSION/SIGNIFICANCE OF IMPACT: Our mouse model of radiation-induced cardiotoxicity has the potential to shift current preclinical research paradigms to more closely mimic the radiation plans most commonly administered in clinical practice. The primary technologic innovation to be developed here is the use of the SARRP to deliver image-guided, in situ, focal radiation to a defined portion of the mouse heart. From a conceptual perspective, we propose a novel approach for phenotyping radiation-induced cardiac damage in patients undergoing chest radiation therapy, integrating sensitive radiomic and biochemical markers into a predictive model of cardiotoxicity.

Ultraviolet B irradiation increases the expression of trichohyalin-like 1 protein in human skin xenotransplants.

Trichohyalin-like (TCHHL)1 is a member of the fused-type S100 protein family. Its function remains unknown, although it has been reported to be expressed in the basal layer of the normal epidermis. The aim of this study was to investigate the effects of ultraviolet B (UVB) irradiation on the expression of TCHHL1 in human skin xenotransplants. Expression of TCHHL1 mRNA was increased in the UVB-exposed skin 2 days after UVB irradiation. TCHHL1 was immunohistochemically detected in the basal layers after sham irradiation. However, on Day 2 after irradiation, the TCHHL1 signals were spread throughout the basal and spinous layers of the irradiated skin, with increased expression of cytokeratin 14 and a dramatic increase in the number of Ki67-positive cells observed. These results show that TCHHL1 is a novel protein whose expression can be increased by UVB irradiation. In addition, this study experimentally shows that TCHHL1 is expressed in proliferative keratinocytes.

To Evaluate the Efficacy of 780 nm Low Level Laser Therapy for the Treatment of Plantar Fasciitis in South Western Ethiopia

Objective: By definition plantar fasciitis (PF)is an inflammation of the plantar fascia. Present study evaluates the effects of 780 nm Low Level Laser Therapy (LLLT)in the treatment of plantarfasciitis &establishes the status of LLLT as a cost effective modality for the treatment of plantar fasciitis. Method: 80 subjects were selected on the basis of the inclusion and exclusion criteria andwere recruited randomly to either 780nm LLLT (experimental group) or sham irradiation (placebo control group). Result: Overall results showed significant difference in Visual Analogue Scale (VAS), Foot Function Index (FFI) andDorsiflexion (DF) from 0 week to 4th week inGroup A indicating that the rate of improvement in Group A was more than Group B. Hence concluding the positive contribution of therapeutic modality for pain relief, increasing functional ability and increasing dorsiflexion Range of Motion(ROM) Conclusion: The present study finds that LLLT at the parameters shown is a safe, potent and cost effective conservative treatment method for the patients having plantar fasciitis.

Protective effects of genistein and melatonin on mouse liver injury induced by whole-body ionising radiation.

The aim of the present study was to investigate the effectiveness of melatonin and genistein in preventing radiation therapy (RT)-induced liver injury in mice. A total of 70 Swiss Albino male mice were divided into 7 equal groups (n=10/group) as follows: Melatonin (M group, G3), genistein (G group, G4), polyethylene glycol-400 (P group, G5), RT only (RT group, G2) and sham irradiation (C group, G1). RT plus genistein (RT+G group, G7) and RT plus melatonin (RT+M group, G6) were the co-treatment groups. Firstly, hepatic tissue damage was induced in mice via exposure to a single dose of 6-Gy irradiation. RT was performed with a cobalt-60 teletherapy machine (80 cm fixed source-to-surface distance, 2.5-cm depth). Melatonin was processed (100 mg/kg, intraperitoneal) 30 min before and genistein was administered (200 mg/kg, SC) one day prior to the single dose of irradiation. Six months following irradiation, all mice were sacrificed. The degree of liver injury was measured using histological liver sections. Liver injury was significantly worse in the RT group than in the control group (C; RT vs. C; P<0.05); however, liver injury decreased following co-treatment with melatonin or genistein vs. RT alone (RT+M and RT+G vs. RT; P<0.05). No difference was observed between the RT+M and RT+G groups (P>0.05). The present study revealed that melatonin and genistein administration prior to irradiation protects mice against liver injury, which may have therapeutic implications for RT-induced injuries.

Radiation of salivary glands to reduce drooling in patients with Parkinson: a double-blind RCT

Drooling is a common symptom in patients with Parkinson’s disease causing physical and emotional distress. It is unknown which major salivary glands are the best candidates for irradiation to reduce drooling with minimal adverse events. Therefore, this study assessed the efficacy and safety of submandibular and parotid salivary gland irradiation to reduce drooling. Patients with parkinsonism and severe drooling according to the Unified Parkinson Disease Rating Scale (UPDRS) were asked to join a prospective, randomized, double-blind, placebo-controlled trial assessing the effect of salivary gland irradiation on drooling. Exclusion criteria were use of anticholinergic drugs, salivary gland diseases, and a history of (pre)malignancy. After obtaining informed consent, patients were randomized for parotid irradiation, submandibular- and sham irradiation (2x6 Gy with one-week interval). After 6 months, sham irradiated patients were actively irradiated. Patients were evaluated at 1, 3, 6, and 12 months after radiation. Primary outcome was drooling severity according to UPDRS. Secondary outcomes were effects on stimulated glandular salivary secretion rates and adverse effects (e.g. xerostomia and sticky saliva). Between October 13, 2010 and October 28, 2015, 31 eligible patients could be included. Eleven patients were radiated on the parotid glands, 10 patients on the submandibular glands and 10 patients were sham irradiated. One patient irradiated on the parotid glands discontinued participation after three months due to physical deterioration. At six months, irradiation of parotid or submandibular glands significantly reduced drooling subjectively according to UPDRS (p < 0.001 and p = 0.011) compared to placebo treatment. Parotid and submandibular irradiation also significantly decreased salivary secretion rates equally effective, but more patients irradiated on submandibular glands experienced sticky saliva (at six months: 33% vs. 13%). Major salivary glands irradiation reduces drooling in patients with Parkinson’s disease. Parotid gland irradiation is accompanied by fewer side effects and thus preferred.

System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta).

We developed a clinical assessment tool for use in an NHP radiation model to 1) quantify severity responses for subsyndromes of the acute radiation syndrome (ARS; that is, hematopoietic and others) and 2) identify animals that required enhanced monitoring. Our assessment tool was based primarily on the MEdical TREatment ProtocOLs for Radiation Accident Victims (METREPOL) scoring system but was adapted for NHP to include additional indices (for example, behaviors) for use in NHP studies involving limited medical intervention. Male (n = 16) and female (n = 12) rhesus macaques (Macaca mulatta; 5 groups: sham and 1.0, 3.5, 6.5, and 8.5 Gy; n = 6 per group) received sham- or bilateral 60Co γ-irradiation at approximately 0.6 Gy/mn. Clinical signs of ARS and blood analysis were obtained before and serially for clinical assessment during the period of 6 h to 60 d after sham or 60Co irradiation. Minimal supportive care (that is, supplemental nutrition, subcutaneous fluid, loperamide, acetaminophen, and topical antibiotic ointment) was prescribed based on clinical observations. Results from clinical signs and assays for assessment of relevant organ systems in individual animals were stratified into ARS severity scores of normal (0), mild (1), moderate (2), and severe (3 or 4). Individual NHP were scored for maximal subsyndrome ARS severity in multiple organ systems by using the proposed ARS scoring system to obtain an overall ARS response category. One NHP died unexpectedly. The multiple-parameter ARS severity scoring tool aided in the identification of animals in the high-dose (6.5 and 8.5 Gy) groups that required enhanced monitoring.

18F-Flortanidazole Hypoxia PET Holds Promise as a Prognostic and Predictive Imaging Biomarker in a Lung Cancer Xenograft Model Treated with Metformin and Radiotherapy.

Metformin may improve tumor oxygenation and thus radiotherapy response, but imaging biomarkers for selection of suitable patients are still under investigation. First, we assessed the effect of acute metformin administration on non-small cell lung cancer xenograft tumor hypoxia using PET imaging with the hypoxia tracer 18F-flortanidazole. Second, we verified the effect of a single dose of metformin before radiotherapy on long-term treatment outcome. Third, we examined the potential of baseline 18F-flortanidazole as a prognostic or predictive biomarker for treatment response. Methods: A549 tumor-bearing mice underwent a 18F-flortanidazole PET/CT scan to determine baseline tumor hypoxia. The next day, mice received a 100 mg/kg intravenous injection of metformin. 18F-flortanidazole was administered intravenously 30 min later, and a second PET/CT scan was performed to assess changes in tumor hypoxia. Two days later, the mice were divided into 3 therapy groups: controls (group 1), radiotherapy (group 2), and metformin + radiotherapy (group 3). Animals received saline (groups 1-2) or metformin (100 mg/kg; group 3) intravenously, followed by a single radiotherapy dose of 10 Gy (groups 2-3) or sham irradiation (group 1) 30 min later. Tumor growth was monitored triweekly by caliper measurement, and tumor volume relative to baseline was calculated. The tumor doubling time (TDT), that is, the time to reach twice the preirradiation tumor volume, was defined as the endpoint. Results: Thirty minutes after metformin treatment, 18F-flortanidazole demonstrated a significant change in tumor hypoxia, with a mean intratumoral reduction in 18F-flortanidazole tumor-to-background ratio (TBR) from 3.21 ± 0.13 to 2.87 ± 0.13 (P = 0.0001). Overall, relative tumor volume over time differed across treatment groups (P < 0.0001). Similarly, the median TDT was 19, 34, and 52 d in controls, the radiotherapy group, and the metformin + radiotherapy group, respectively (log-rank P < 0.0001). Both baseline 18F-flortanidazole TBR (hazard ratio, 2.0; P = 0.0004) and change from baseline TBR (hazard ratio, 0.39; P = 0.04) were prognostic biomarkers for TDT irrespective of treatment, and baseline TBR predicted metformin-specific treatment effects that were dependent on baseline tumor hypoxia. Conclusion: Using 18F-flortanidazole PET imaging in a non-small cell lung cancer xenograft model, we showed that metformin may act as a radiosensitizer by increasing tumor oxygenation and that baseline 18F-flortanidazole shows promise as an imaging biomarker.

Evaluation of the Effect of Topical Application of Nigella sativa on Acute Radiation-Induced Nasal Mucositis.

The goal of this study was to demonstrate the effect of radiotherapy (RT) on nasal mucosa in rats and to evaluate the radioprotective effects of the topical application of black seed oil (Nigella sativa [NS]) to treat acute radiation-induced nasal mucositis.A total of 18 rats were randomized into 3 groups, with 6 animals per group. The rats in group 1 were topically administered saline in the nasal cavity after sham irradiation. Group 2 received saline at the same dose after irradiation. Group 3 was given NS after irradiation. The rats in groups 2 and 3 were irradiated with a single dose of 40 Gy to the nasal and paranasal area. Only one drop of saline (0.05 mL) was applied to each nostril in the first, second, and third days after RT in groups 1 and 2. One drop of cold press NS (0.05 mL) was applied to each nostril in group 3. Fourteen days after irradiation, the nasal mucosal tissues were excised for histopathological evaluation. Vascular dilatation, inflammatory cell infiltration, superficial erosion, and formation of exudates were classified according to the severity.No evidence of mucositis was observed in group 1. Of all the parameters the only statistically significant difference between groups 2 and 3 were observed for "superficial erosion' (P < 0.05). Overall microscopic observations in the NS-treated group were better than in group 2.The preliminary results of our study have shown that local application of NS to the nasal mucosa may be an effective treatment of acute nasal mucositis due to RT.

NOS2 deficiency has no influence on the radiosensitivity of the hematopoietic system

ObjectivePrevious studies have shown that inhibition of inducible NO synthase (NOS2 or iNOS) with an inhibitor can selectively protect several normal tissues against radiation during radiotherapy. However, the role of NOS2 in ionizing radiation (IR)-induced bone marrow (BM) suppression is unknown and thus was investigated in the present study using NOS2−/− and wild-type mice 14 days after they were exposed to a sublethal dose of total body irradiation (TBI).MethodsThe effects of different doses of IR (1, 2 and 4 Gy) on the apoptosis and colony-forming ability of bone marrow cells from wild-type (WT) and NOS2−/− mice were investigated in vitro. In addition, we exposed NOS2−/− mice and WT mice to 6-Gy TBI or sham irradiation. They were euthanized 14 days after TBI for analysis of peripheral blood cell counts and bone marrow cellularity. Colony-forming unit-granulocyte and macrophage, burst-forming unit-erythroid and CFU-granulocyte, erythroid, macrophage in bone marrow cells from the mice were determined to evaluate the function of hematopoietic progenitor cells (HPCs), and the ability of hematopoietic stem cells (HSCs) to self-renew was analysed by the cobblestone area forming cell assay. The cell cycling of HPCs and HSCs were measured by flow cytometry.ResultsExposure to 2 and 4 Gy IR induced bone marrow cell apoptosis and inhibited the proliferation of HPCs in vitro. However, there was no difference between the cells from WT mice and NOS2−/− mice in response to IR exposure in vitro. Exposure of WT mice and NOS2−/− mice to 6 Gy TBI decreased the white blood cell, red blood cell, and platelet counts in the peripheral blood and bone marrow mononuclear cells, and reduced the colony-forming ability of HPCs (P < 0.05), damaged the clonogenic function of HSCs. However, these changes were not significantly different in WT and NOS2−/− mice.ConclusionThese data suggest that IR induces BM suppression in a NOS2-independent manner.