Assessment of Blood Pressure in Irradiated Rhesus Macaques (Macaca mulatta).

There is increasing evidence that circulatory disease incidence and mortality is associated with radiation exposure. Wake Forest School of Medicine is home to a unique cohort of total-body irradiated macaques, some with evidence of vascular end-organ disease in the brain, kidney and heart. Because there is a link between high blood pressure and vascular disease in all these sites, we undertook a retrospective study to evaluate blood pressure and radiation in this cohort of animals. In this work, we utilized a cohort of nonhuman primates (rhesus macaques, Macaca mulatta) long-term survivors of high-dose total-body irradiation (1.1-8.5 Gy, N = 129) and controls (N = 37) to evaluate the effects of radiation on blood pressure and obesity. Subjects were between 3 and 22 years of age (median 9 years). Blood pressure (BP) was measured 1-14 years postirradiation (median 4 years). Subjects were sedated with a combination of ketamine HCl (15 mg/kg body weight, IM) and midazolam (0.1 mg/kg body weight, IM) and systolic, diastolic, and mean arterial pressures were measured using a high definition oscillometer. Obesity was defined by dual energy X-ray absorptiometry as a body fat percentage >35%. Statistical analysis of the collected data indicated significant increases in blood pressure with increasing age and obesity. However, radiation did not significantly alter blood pressure in irradiated animals relative to controls, radiation dose, or age of irradiation.

Local Irradiation of Mouse Tooth Germ Gives Insight into the Direct Effects of Irradiation on Root Development.

To elucidate the mechanism underlying the failure of root formation after irradiation, we established a method of local irradiation of the molar tooth germ and demonstrated that radiation directly affected dental root development. In the current study, to locally irradiate the lower first molars of 5-day-old C57BL/6J mice, we used lead glass containing a hole as a collimator. We confirmed that our local irradiation method targeted only the tooth germ. The irradiated root was immature in terms of apical growth, and dentin formation was irregular along the outside of the root apices. Moreover, calcified tissue apically surrounded Hertwig's epithelial root sheath, which disappeared abnormally early. This method using a local irradiation experimental model will facilitate research into radiation-induced disorders of dental root formation.

A Study to Assess the Dosimetric Impact of the Anatomical Changes Occurring in the Parotid Glands and Tumour Volume during Intensity Modulated Radiotherapy using Simultaneous Integrated Boost (IMRT-SIB) in Head and Neck Squamous Cell Cancers.

BACKGROUND: Anatomical variations in head and neck cancer during IMRT leads to volume shrinkage, results in dosimetric variations in tumour and normal tissue including parotid glands, with a risk of radiation toxicities. METHODS: 30 patients with a stage II-IV head and neck squamous cell carcinoma (HNSCC) were treated with definitive IMRT-SIB and concomitant chemotherapy. Volumetric and dosimetric variations were evaluated during the period of IMRT by recalculating and obtaining dose-volume histograms of re-contoured target volumes and parotid glands on repeat CT scans taken multiple times during treatment (CT1, CT2, CT3 and CT4). RESULTS: Result showed significant (p < 0.001) mean decrease in both primary and nodal tumors volume with time whereas increase (p < 0.01 or p < 0.001) in respective V100 (%) and D2% (Gy). The mean parotid gland dose increased (p < 0.01 or p < 0.001) with time, whereas parotid gland volume and distance between plan isocenter and centre of mass of parotid glands decreased (p < 0.05 or p < 0.001) with time. Patient's mean weight and neck circumference both decrease (p < 0.001) with time whereas ECOG score increase (p < 0.001) with time. The mucosal toxicity increased significantly (p < 0.001) with time. The change in both weight and neck circumference showed significant (p < 0.001) and direct (positive correlation) association with change in parotid gland volume. CONCLUSION: If the PTV and normal anatomy are changing with time, adaptive IMRT would be beneficial radiation dose delivery where possible.

Effects of far infrared light on Alzheimer's disease-transgenic mice.

Far infrared light has been used in many medical procedures. However, the detailed biological mechanisms of infrared light's effects have not yet been elucidated. Many researchers have pointed out the thermal effects of treatments such as infrared saunas, which are known to increase blood flow. Alzheimer's disease (AD) is associated with gradual decreases in brain blood flow and resulting dementia. In this study, we attempted to clarify the beneficial effects of far infrared light using the 5xFAD mouse, a transgenic model of AD. We exposed 5xFAD mice to far infrared light for 5 months. Among the far infrared-exposed AD mice, body weights were significantly decreased, and the levels of nerve growth factor and brain-derived neurotrophic factor protein were significantly increased in selected brain areas (compared to those in non-irradiated AD mice). However, cognition and motor function (as assessed by Morris water maze and Rota Rod tests, respectively) did not differ significantly between the irradiated and non-irradiated AD mouse groups. These results indicated that exposure to far infrared light may have beneficial biological effects in AD mice. However, the experimental schedule and methods may need to be modified to obtain clearer results.

PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.

Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and -citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral -citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with -citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and -citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds.

Late Health Effects of Partial Body Irradiation Injury in a Minipig Model Are Associated with Changes in Systemic and Cardiac IGF-1 Signaling.

Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9-2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.

Differential normal skin transcriptomic response in total body irradiated mice exposed to scattered versus scanned proton beams.

Proton therapy allows to avoid excess radiation dose on normal tissues. However, there are some limitations. Indeed, passive delivery of proton beams results in an increase in the lateral dose upstream of the tumor and active scanning leads to strong differences in dose delivery. This study aims to assess possible differences in the transcriptomic response of skin in C57BL/6 mice after TBI irradiation by active or passive proton beams at the dose of 6 Gy compared to unirradiated mice. In that purpose, total RNA was extracted from skin samples 3 months after irradiation and RNA-Seq was performed. Results showed that active and passive delivery lead to completely different transcription profiles. Indeed, 140 and 167 genes were differentially expressed after active and passive scanning compared to unirradiated, respectively, with only one common gene corresponding to RIKEN cDNA 9930021J03. Moreover, protein-protein interactions performed by STRING analysis showed that 31 and 25 genes are functionally related after active and passive delivery, respectively, with no common gene between both types of proton delivery. Analysis showed that active scanning led to the regulation of genes involved in skin development which was not the case with passive delivery. Moreover, 14 ncRNA were differentially regulated after active scanning against none for passive delivery. Active scanning led to 49 potential mRNA-ncRNA pairs with one ncRNA mainly involved, Gm44383 which is a miRNA. The 43 genes potentially regulated by the miRNA Gm44393 confirmed an important role of active scanning on skin keratin pathway. Our results demonstrated that there are differences in skin gene expression still 3 months after proton irradiation versus unirradiated mouse skin. And strong differences do exist in late skin gene expression between scattered or scanned proton beams. Further investigations are strongly needed to understand this discrepancy and to improve treatments by proton therapy.

Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation.

BACKGROUND AND PURPOSE: Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings. MATERIALS AND METHODS: Male CBA/CaJ mice fed either a methionine-adequate diet or MSD (6.5 mg methionine/kg diet vs 19.5 mg/kg) received localized abdominal X-irradiation (220 kV, 13 mA) using the Small Animal Radiation Research Platform, and tissues were harvested 4, 7, and 10 days after irradiation. RESULTS: MSD exacerbated gastrointestinal toxicity after local abdominal irradiation with 12.5 Gy. This was evident as impaired nutrient absorption was paralleled by reduced body weight recovery. Mechanistically, significant shifts in the gut ecology, evident as decreased microbiome diversity, and substantially increased bacterial species that belong to the genus Bacteroides triggered proinflammatory responses. The latter were evident as increases in circulating neutrophils with corresponding decreases in lymphocytes and associated molecular alterations, exhibited as increases in mRNA levels of proinflammatory genes Icam1, Casp1, Cd14, and Myd88. Altered expression of the tight junction-related proteins Cldn2, Cldn5, and Cldn6 indicated a possible increase in intestinal permeability and bacterial translocation to the liver. CONCLUSIONS: We report that dietary supplementation with methionine exacerbates gastrointestinal syndrome in locally irradiated mice. This study demonstrates the important roles registered dieticians should play in clinical oncology and further underlines the necessity of preclinical and clinical investigations in the role of diet in the success of cancer therapy.

Nutrition impact symptoms and weight loss in head and neck cancer during radiotherapy: a longitudinal study.

OBJECTIVE: Patients with head and neck cancer (HNC) receiving radiotherapy (RT) are at high risk of weight loss (WL) due to a variety of nutrition impact symptoms (NIS). This study aimed to describe the NIS through the Head and Neck patient Symptom Checklist and body weight over time and further explore the impact of NIS on WL in patients with HNC undergoing RT. METHODS: This was a prospective, longitudinal observational study. NIS and body weight of 117 participants were assessed at baseline, mid-treatment and post-treatment of RT. Generalised estimation equations (GEE) were used to conduct repeated measures analysis of NIS interference score and body weight at each time point and estimate the impact of NIS interference score on WL. RESULTS: All participants experienced a substantial increase in the mean number of NIS during RT, with each patient having eight to nine NIS at mid-treatment and post-treatment. Marked increases were noted in almost each NIS score during RT. Compared with their baseline body weight, 97 (82.9%) and 111 (94.9%) participants experienced WL at mid-treatment and post-treatment, with the mean WL of 2.55±1.70 kg and 5.31±3.18 kg, respectively. NIS of dry mouth (ß=-0.681, p=0.002, 95% CI -1.116 to -0.247), difficulty swallowing (ß=-0.410, p=0.001, 95% CI -0.651 to -0.169) and taste change (ß=-0.447, p=0.000, 95% CI -0.670 to -0.225) impacted WL significantly in GEE multivariate model. CONCLUSIONS: Patients with HNC experience a variety of NIS which have significant impact on WL during RT. Assessment of NIS, especially dry mouth, difficulty swallowing and taste change, should be given more considerable attention in the supportive care of patients with HNC.

Photodynamic treatment with purpurin 18 effectively inhibits triple negative breast cancer by inducing cell apoptosis.

This study aims to evaluate the photodynamic efficacy of purpurin 18 (pu-18) on triple negative breast cancer both in vitro and in vivo. Two states of 4T1 cells, 2D culture and 3D spheroids, were used to evaluate the photodynamic action of pu-18 in vitro. The in vitro study results indicated that for the 4T1 2D cell culture, the photodynamic therapy (PDT) treatment showed significant photocytotoxicity at low pu-18 concentrations following light irradiation. Pu-18 was found to distribute on the lysosomes, mitochondria, Golgi apparatus, and endoplasmic reticulum. After irradiation, pu-18 can generate ROS to destroy the mitochondrial membrane potential (MMP) and eventually induce apoptosis in the 2D 4T1 cells. Light-activated pu-18 could also induce the destruction of the 3D 4T1 cell spheroids. The in vivo study was conducted by using a subcutaneous 4T1 breast cancer animal model. The results demonstrated that pu-18 could remain in the tumor for more than 4 days by direct intra-tumoral injection. The PDT treatment was performed every 2 days for a total of 3 times. The results showed that PDT treatment could significantly inhibit tumor growth in vivo, indicating a good photodynamic efficacy of pu-18 in the mouse breast cancer model, without influencing weight and major organ function. The survival pattern results showed that PDT treatment could largely extend the survival time of mice with breast cancer. The preliminary conclusion is that photodynamic treatment using pu-18 is effective at preventing the growth of triple negative breast cancer cells both in vitro and in vivo. A combination of light irradiation and pu-18 could therefore be a worthwhile approach for the treatment of triple negative breast cancer.

The effect of supplementary ultraviolet wavelengths on the performance of broiler chickens.

Qualities of the light environment, such as the spectral composition of light, have been shown to impact growth and performance of broiler chickens. UVA light is visible to broiler chickens, whereas UVB wavelengths promote endogenous vitamin D synthesis, which could support their rapid development. The aim of the current study was to investigate the impacts of supplementary UVA and UVB wavelengths on performance indicators of broiler chickens. Day-old Ross 308 chicks (n = 638), reared to a target stocking density of 33 kg/m2, were randomly assigned to 1 of 3 lighting treatments: A) White light emitting diode (LED) and supplementary UVA LED lighting (18-h photoperiod); B) White LED with supplementary UVA and UVB fluorescent lighting providing 30 µW/cm2 UVB at bird level (lights on for 8 h of the total photoperiod to avoid overexposure of UVB); and C) White LED control group, representative of farm conditions (18-h photoperiod). Mortality was recorded, and broiler chickens were individually weighed at 8, 15, 22, 27, and 34 D of age. Generalized linear models and nonlinear mixed effects models (Gompertz curve) were fitted to determine the effects of UV wavelengths on broiler mortality and growth performance. UV did not impact breast or leg weight of broiler chickens but was associated with differences in mortality, growth, and end weight. Broiler chickens provided with UVA for the full 18-h photoperiod had slower initial growth than control broilers and a reduction in mortality. Results from male broilers reared with supplementary UVA + UVB for 8 h indicated they could reach finishing weights sooner than controls, which supports the potential for UVA + B to improve the growth performance of males. Results suggest that the provision of supplementary UVA + UVB wavelengths may improve the performance of male broiler chickens. The reduction in mortality in the UVA only treatment may warrant further investigation. The inclusion of UV wavelengths within poultry lighting regimes represents a promising area of further study.

Evaluation of light colour manipulation on physiological response and growth performance of broiler chickens.

Artificial illumination, including light quality, is crucial in modern broiler management. The aim of this study was to examine the effect of a switch in light colour on the performance of broiler chickens in tropical environments. A total of 280 1-day-old Arbor acre male chicks were used for this study and were weighed and assigned to different light environments viz. white (WH), green (GR), blue (BL), GR switched to BL at 14 days (GB), BL switched to GR at 14 days (BG), BL switched to GR at 28 days (BGG) and GR switched to BL at 28 days (GBB) having four replicates of ten birds each. Body weight, weight gain, feed intake and feed conversion ratio were recorded weekly. Blood samples were collected from 2 birds per replicate weekly for the determination of plasma triiodothyronine (T3), haematology and serum biochemical parameters. The experiment was laid out in a completely randomised design. Results showed that the final body weights of the birds in GBB and GB were comparable but higher than those of the other treatment groups. Feed intake of the chickens in WH was similar to that of BG but higher than those of the other treatment groups, while FCR of the birds in WH was higher (P < 0.05) than the other treatment groups. Plasma T3 of the birds in GR was comparable to that of birds in BL but significantly higher than those of the birds in WH and a similar trend was also observed at weeks 1 and 2. Heterophil/lymphocyte ratio (H/L) of the birds in WH was significantly higher than those of BL and GR whose values were similar to those in GB and BG. Heterophil/lymphocytes of the birds in WH was higher than those of BG, GR, BGG, GB and GBB but similar to those of BL. The breast muscle of the birds in GBB and GB was similar to those of BGG and GR and significantly higher than those of WH, BL and BG. Based on the results obtained in this study, it was concluded that the use of green light up to 28 days in combination with blue light stimulated the growth of broiler chickens and manipulation of light colours can be used to improve the welfare and performance of chickens.

Gut microbiota response to ionizing radiation and its modulation by HDAC inhibitor TSA.

AIM: Trichostatin A (TSA) has been shown to mitigate whole body γ-radiation-induced morbidity and mortality. The current study aimed at studying the effects of TSA post-irradiation treatment on gut-microbiota, especially the translocation of the microbes from the intestine to other organs in C57 Bl/6 mice model. MATERIALS AND METHODS: On 1st, 3rd 5th 7th 9th 12th and 14th days after various treatments bacteria were isolated from the intestine and nearby organs (mesenteric lymph node, spleen and liver) for further analysis. The jejunum part of all animals was processed for histological analysis. RESULTS: The group radiation + drug showed reduced susceptibility to radiation injury as well as microbiota related anomalies compared to the irradiated alone group. This was described by increased microflora in different parts of the GI tract in the radiation + drug group compared to the irradiated group and reduced histopathological damages in the jejunum. Also, a reduced percentage of translocated bacteria were found in different organs of radiation + drug group animals. CONCLUSION: TSA treatment post-irradiation could effectively control bacterial translocation as well as GI injury in mice.

Size-Specific Dose Estimates of Radiation Based on Body Weight and Body Mass Index for Chest and Abdomen-Pelvic CTs.

BACKGROUND: To correlate body weight, body mass index (BMI), and water-equivalent diameter (d w) and to assess size-specific dose estimates (SSDEs) based on body weight and BMI for chest and abdomen-pelvic CT examinations. METHODS: An in-house program was used to calculate d w, size-dependent conversion factor (f), and SSDE for 1178 consecutive patients undergoing chest and abdomen-pelvic CT examinations. Associations among body weight, BMI, and d w were determined, and linear equations were generated using linear regression analysis of the first 50% of the patient population. SSDEs (SSDEweight and SSDEBMI) were calculated based on body weight and BMI as d w surrogates on the second 50% of the patient population. Mean root-mean-square errors of SSDEweight and SSDEBMI were computed with SSDE from the axial images as reference values. RESULTS: Both body weight and BMI correlated strongly with d w for the chest (r = 0.85, 0.87, all p < 0.001) and abdomen-pelvis (r = 0.85, 0.86, all p < 0.001). Mean values of SSDEweight and SSDEBMI based on the linear equations for body weight, BMI, and d w were in close agreement with SSDE from the axial images, with overall mean root-mean-square errors of 0.62 mGy (6.10%) and 0.57 mGy (5.65%), for chest, and 0.76 mGy (5.61%) and 0.71 mGy (5.22%), for abdomen-pelvis, respectively. CONCLUSIONS: Both body weight and BMI, serving as d w surrogates, can be used to calculate SSDEs in the chest and abdomen-pelvis CT examinations, providing values comparable to SSDEs from the axial images, with an overall mean root-mean-square error of less than 0.76 mGy or 6.10%.

Ramipril reduces incidence and prolongates latency time of radiation-induced rat myelopathy after photon and carbon ion irradiation.

To test the hypothesis that the use of an angiotensin-converting enzyme inhibitor (ACEi) during radiotherapy may be ameliorative for treatment-related normal tissue damage, a pilot study was conducted with the clinically approved (ACE) inhibitor ramipril on the outcome of radiation-induced myelopathy in the rat cervical spinal cord model. Female Sprague Dawley rats were irradiated with single doses of either carbon ions (LET 45 keV/µm) at the center of a 6 cm spread-out Bragg peak (SOBP) or 6 MeV photons. The rats were randomly distributed into 4 experimental arms: (i) photons; (ii) photons + ramipril; (iii) carbon ions and (iv) carbon ions + ramipril. Ramipril administration (2 mg/kg/day) started directly after irradiation and was maintained during the entire follow-up. Complete dose-response curves were generated for the biological endpoint radiation-induced myelopathy (paresis grade II) within an observation time of 300 days. Administration of ramipril reduced the rate of paralysis at high dose levels for photons and for the first time a similar finding for high-LET particles was demonstrated, which indicates that the effect of ramipril is independent from radiation quality. The reduced rate of myelopathy is accompanied by a general prolongation of latency time for photons and for carbon ions. Although the already clinical approved drug ramipril can be considered as a mitigator of radiation-induced normal tissue toxicity in the central nervous system, further examinations of the underlying pathological mechanisms leading to radiation-induced myelopathy are necessary to increase and sustain its mitigative effectiveness.

Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study.

PURPOSE: Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation. MATERIALS AND METHODS: Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, 18F-fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-11C-methyl-4,4'-diaminostilbene (11C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes. RESULTS: Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with 18F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced 18F-FDG uptake on day 94. 11C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, 11C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and 11C-MeDAS uptake was observed in irradiated rats. CONCLUSIONS: Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.

Protective Effect of Alpha-Lipoic Acid on Salivary Dysfunction in a Mouse Model of Radioiodine Therapy-Induced Sialoadenitis.

Radioiodine (RI) therapy is known to cause salivary gland (SG) dysfunction. The effects of antioxidants on RI-induced SG damage have not been well described. This study was performed to investigate the radioprotective effects of alpha lipoic acid (ALA) administered prior to RI therapy in a mouse model of RI-induced sialadenitis. Four-week-old female C57BL/6 mice were divided into four groups (n = 10 per group): group I, normal control; group II, ALA alone (100 mg/kg); group III, RI alone (0.01 mCi/g body weight, orally); and group IV, ALA + RI (ALA at 100 mg/kg, 24 h and 30 min before RI exposure at 0.01 mCi/g body weight). The animals in these groups were divided into two subgroups and euthanized at 30 or 90 days post-RI treatment. Changes in salivary 99mTc pertechnetate uptake and excretion were tracked by single-photon emission computed tomography. Salivary histological examinations and TUNEL assays were performed. The 99mTc pertechnetate excretion level recovered in the ALA treatment group. Salivary epithelial (aquaporin 5) cells of the ALA + RI group were protected from RI damage. The ALA + RI group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Fewer apoptotic cells were observed in the ALA + RI group compared to the RI only group. Pretreatment with ALA before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Conventional dose rate spatially-fractionated radiation therapy (SFRT) treatment response and its association with dosimetric parameters-A preclinical study in a Fischer 344 rat model.

PURPOSE: To identify key dosimetric parameters that have close associations with tumor treatment response and body weight change in SFRT treatments with a large range of spatial-fractionation scale at dose rates of several Gy/min. METHODS: Six study arms using uniform tumor radiation, half-tumor radiation, 2mm beam array radiation, 0.3mm minibeam radiation, and an untreated arm were used. All treatments were delivered on a 320kV x-ray irradiator. Forty-two female Fischer 344 rats with fibrosarcoma tumor allografts were used. Dosimetric parameters studied are peak dose and width, valley dose and width, peak-to-valley-dose-ratio (PVDR), volumetric average dose, percentage volume directly irradiated, and tumor- and normal-tissue EUD. Animal survival, tumor volume change, and body weight change (indicative of treatment toxicity) are tested for association with the dosimetric parameters using linear regression and Cox Proportional Hazards models. RESULTS: The dosimetric parameters most closely associated with tumor response are tumor EUD (R2 = 0.7923, F-stat = 15.26*; z-test = -4.07***), valley (minimum) dose (R2 = 0.7636, F-stat = 12.92*; z-test = -4.338***), and percentage tumor directly irradiated (R2 = 0.7153, F-stat = 10.05*; z-test = -3.837***) per the linear regression and Cox Proportional Hazards models, respectively. Tumor response is linearly proportional to valley (minimum) doses and tumor EUD. Average dose (R2 = 0.2745, F-stat = 1.514 (no sig.); z-test = -2.811**) and peak dose (R2 = 0.04472, F-stat = 0.6874 (not sig.); z-test = -0.786 (not sig.)) show the weakest associations to tumor response. Only the uniform radiation arm did not gain body weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetric parameters except for valley (minimum) dose (R2 = 0.3814, F-stat = 13.56**), valley width (R2 = 0.2853, F-stat = 8.783**), and peak width (R2 = 0.2759, F-stat = 8.382**). CONCLUSIONS: For a single-fraction SFRT at conventional dose rates, valley, not peak, dose is closely associated with tumor treatment response and thus should be used for treatment prescription. Tumor EUD, valley (minimum) dose, and percentage tumor directly irradiated are the top three dosimetric parameters that exhibited close associations with tumor response.

Changes in miRNA expressions in the injured small intestine of mice following high­dose radiation exposure.

The small intestine is one of the most highly regenerative and radiosensitive tissues in mammals, including humans. Exposure to high doses of ionizing radiation causes serious intestinal damage. Recently, several investigations have been conducted using radioprotective agents to determine ways for reducing intestinal damage caused by radiation exposure. However, a thorough understanding of functional changes occurring in the small intestine of mice exposed to high­dose radiation is necessary for developing novel and more potent radioprotective agents. In this study, we examined changes in microRNA (miRNA/miR) expressions in the small intestine of mice at 72 h after X­ray exposure (10 Gy). We identified seven upregulated miRNAs and six downregulated miRNAs in the small intestine of mice following radiation exposure using miRNA microarray analysis. Particularly, miR­34a­5p was highly expressed, which was confirmed by reverse transcription-quantitative PCR. Forkhead box P1 (Foxp1) was predicted to be a target of the mRNA of miR­34a­5p using OmicsNet. Decreased Foxp1 expression in the small intestine following radiation exposure was confirmed, suggesting that Foxp1 expression recovery may induce the suppression of radiation­induced enteritis. Therefore, miR­34a­5p is a potential target molecule for developing novel radioprotective agents.

Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis.

Cold stimuli and the subsequent activation of ß-adrenergic receptor (ß-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the ß3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ß-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.