P7C3 ameliorates barium chloride-induced skeletal muscle injury activating transcriptomic and epigenetic modulation of myogenic regulatory factors.

Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl2) into the tibialis anterior (TA) muscle in C57Bl/6J wild-type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl2-induced TA muscle injury was robust and the P7C3-treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle-treated mice. The specificity of P7C3 was evaluated using Nampt+/- mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA-sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh-treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh-treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation-reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3-treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3-treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl2-injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide-induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis.

Effect of Detector Orientation and Influence of Jaw Position in the Determination of Small-field Output Factor with Various Detectors for High-energy Photon Beams.

Background: Accurate dose measurements are difficult in small fields due to charge particle disequilibrium, partial source occlusion, steep dose gradient, and the finite size of the detector. Aim: The study aims to determine the output factor using various detectors oriented in parallel and perpendicular orientations for three different tertiary collimating systems using 15 MV photon beams. In addition, this study analyzes how the output factor could be affected by different configurations of X and Y jaws above the tertiary collimators. Materials and Methods: Small field output factor measurements were carried out with three detectors for different tertiary collimating systems such as BrainLab stereotactic cones, BrainLab mMLC and Millennium MLC namely. To analyze the effect of jaw position on output factor, measurements have been carried out by positioning the jaws at the edge, 0.25, 0.5, and 1.0 cm away from the tertiary collimated field. Results: The data acquired with 15 MV photon beams show significant differences in output factor obtained with different detectors for all collimating systems. For smaller fields when compared to microDiamond, the SRS diode underestimates the output by up to -1.7% ± 0.8% and -2.1% ± 0.3%, and the pinpoint ion chamber underestimates the output by up to -8.1% ± 1.4% and -11.9% ± 1.9% in their parallel and perpendicular orientation respectively. A large increase in output factor was observed in the small field when the jaw was moved 0.25 cm symmetrically away from the tertiary collimated field. Conclusion: The investigated data on the effect of jaw position inferred that the position of the X and Y jaw highly influences the output factors of the small field. It also confirms that the output factor highly depends on the configuration of X and Y jaw settings, the tertiary collimating system as well as the orientation of the detectors in small fields.

Development and testing of nanoparticles delivery for P7C3 small molecule using injury models.

The use of nanoparticles (NPs) has emerged as a potential tool for safe and effective drug delivery. In the present study, we developed small molecule P7C3-based NPs and tested its efficacy and toxicity along with the tissue specific aptamer-modified P7C3 NPs. The P7C3 NPs were prepared using poly (D, L-lactic-co-glycolic acid) carboxylic acid (PLGA-COOH) polymer, were conjugated with skeletal muscle-specific RNA aptamer (A01B P7C3 NPs) and characterized for its cytotoxicity, cellular uptake, and wound healing in vitro. The A01B P7C3 NPs demonstrated an encapsulation efficiency of 30.2 ± 2.6%, with the particle size 255.9 ± 4.3 nm, polydispersity index of 0.335 ± 0.05 and zeta potential of + 10.4 ± 1.8mV. The FTIR spectrum of P7C3 NPs displayed complete encapsulation of the drug in the NPs. The P7C3 NPs and A01B P7C3 NPs displayed sustained drug release in vitro for up to 6 days and qPCR analysis confirmed A01B aptamer binding to P7C3 NPs. The C2C12 cells viability assay displayed no cytotoxic effects of all 3 formulations at 48 and 72 h. In addition, the cellular uptake of A01B P7C3 NPs in C2C12 myoblasts demonstrated higher uptake. In vitro assay mimicking wound healing showed improved wound closure with P7C3 NPs. In addition, P7C3 NPs significantly decreased TNF-α induced NF-κB activity in the C2C12/NF-κB reporter cells after 24-hour treatment. The P7C3 NPs showed 3-4-fold higher efficacy compared to P7C3 solutions in both wound-closure and inflammation assays in C2C12 cells. Furthermore, the P7C3 NPs showed 3-4-fold higher efficacy in reducing the infarct size and protected mouse hearts from ex vivo ischemia-reperfusion injury. Overall, this study demonstrates the safe and effective delivery of P7C3 NPs.

Genetic deletion of Kvß2 (AKR6) causes loss of muscle function and increased inflammation in mice.

The voltage-gated potassium channels (Kv) are complex ion channels with distinct roles in neurotransmission, electrical conductivity of the heart, and smooth and striated muscle functions. Previously, we demonstrated that deletion of Kvß2 in mice results in decreased Pax7 protein levels, hindlimb muscles and body weights, and fiber type switching. In the present study, we tested the hypothesis that Kvß2 regulates skeletal muscle function in mice. The young and old Kvß2 knockout (KO) and wildtype (WT) mice were utilized to test the aging phenotype and skeletal muscle function. Consistent with our previous finding, we found a significant reduction in hindlimb skeletal muscles mass and body weight in young Kvß2 KO mice, which was also significantly reduced in old Kvß2 KO mice compared with age-matched WT mice. Forelimb grip strength, and the hindleg extensor digitorum longus (EDL) muscles force-frequency relations were significantly decreased in young and old Kvß2 KO mice compared to age-matched WT mice. Analysis of transmission electron microscopy images of EDL muscles in young mice revealed a significant reduction in the sarcomere length for Kvß2 KO vs. WT. Hematoxylin and eosin-stained tibialis anterior muscles cryosections displayed a significant decrease in the number of medium (2,000-4,000 µm2) and largest (>4,000 µm2) myofibers area in young Kvß2 KO vs. WT mice. We also found a significant increase in fibrotic tissue area in young Kvß2 KO mice compared with age-matched WT mice. Analysis of RNA Seq data of the gastrocnemius muscles (GAS) identified significant increase in genes involved in skeletal muscle development, proliferation and cell fate determination, atrophy, energy metabolism, muscle plasticity, inflammation, and a decrease in circadian core clock genes in young Kvß2 KO vs. WT mice. Several genes were significantly upregulated (384 genes) and downregulated (40 genes) in young Kvß2 KO mice compared to age-matched WT mice. Further, RT-qPCR analysis of the GAS muscles displayed a significant increase in pro-inflammatory marker Il6 expression in young Kvß2 KO mice compared to age-matched WT mice. Overall, the present study shows that deletion of Kvß2 leads to decreased muscles strength and increased inflammation.

Evaluation of improvements in plan quality with Photon Optimizer v16.1 for single brain lesion SRS treatment.

Background: The purpose of this study is to compare the performance of the Photon Optimizer (PO) version 16.1 algorithm with its earlier version PO v13.6 and with Progressive Resolution Optimizer (PRO) version 13.6 algorithms. Materials and methods: 20 patients with single brain lesions treated with the stereotactic radiosurgery (SRS) technique were retrospectively selected for this study. Initially, for all patients volumetric modulated arc therapy (VMAT) SRS plans were generated with the PRO v 13.6 algorithm. Then, all the plans were re-generated with two versions 13.6 and 16.1 of PO algorithm using the same setup and dose-volume optimization objectives as that of PRO with a similar planning approach. The quality of the generated plans was analysed using ICRU 91 plan evaluation parameters and also using dice similarity co-efficient (DSC), centre of mass distance (CMD) between target and prescription isodose line, Monitor units (MU) and brain-gross tumor volume (GTV) 12 Gy volume. Paired Student t-test was used for statistical analysis with 0.05 as a significant value. Results: PO v16.1 improved all the dosimetric parameters studied compared to PO 13.6, the difference is statistically significant for all the parameters (p < 0.05), except for median dose and brain-GTV 12 Gy volume. PO v16.1 also showed statistically significant improvement for all the dosimetric parameters evaluated, except DSC and conformity index (CI), compared to PRO v13.6. Conclusion: The PO v16.1 generated plans are dosimetrically superior to PO v13.6 and PRO v13.6 in terms of target dose coverage and dose gradient with lesser beam modulation and plan complexity for single brain lesion SRS.

Cardioprotective Effects of 1-(3,6-Dibromo-carbazol-9-yl)-3-Phenylamino-Propan-2-Ol in Diabetic Hearts via Nicotinamide Phosphoribosyltransferase Activation.

Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD+ salvage pathway and is dysregulated in diabetes. Nampt activation results in rescued NADH/NAD+ ratios and provides pharmacological changes necessary for diabetic cardioprotection. Computer docking shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) allows for enhanced Nampt dimerization and association. To test the pharmacological application, we used male leptin receptor-deficient (db/db) mice and treated them with Nampt activator P7C3. The effects of 4-week P7C3 treatment on cardiac function were evaluated along with molecular signaling changes for phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS), and sirtuin 1 (SIRT1). The cardiac function evaluated by ECG and echocardiography were significantly improved after 4 weeks of P7C3 treatment. Biochemically, higher NADH/NAD+ ratios in diabetic hearts were rescued by P7C3 treatment. Moreover, activities of Nampt and SIRT1 were significantly increased in P7C3-treated diabetic hearts. P7C3 treatment significantly decreased the blood glucose in diabetic mice with 4-week treatment as noted by glucose tolerance test and fasting blood glucose measurements compared with vehicle-treated mice. P7C3 activated Nampt enzymatic activity both in vitro and in the 4-week diabetic mouse hearts, demonstrating the specificity of the small molecule. P7C3 treatment significantly enhanced the expression of cardioprotective signaling of p-AKT, p-eNOS, and Beclin 1 in diabetic hearts. Nampt activator P7C3 allows for decreased infarct size with decreased Troponin I and lactose dehydrogenase (LDH) release, which is beneficial to the heart. Overall, the present study shows that P7C3 activates Nampt and SIRT1 activity and decreases NADH/NAD+ ratio, resulting in improved biochemical signaling providing cardioprotection. SIGNIFICANCE STATEMENT: This study shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) is effective in treating diabetes and cardiovascular diseases. The novel small molecule is antiarrhythmic and improves the ejection fraction in diabetic hearts. The study successfully demonstrated that P7C3 decreases the infarct size in hearts during myocardial infarction and ischemia-reperfusion injury. Biochemical and cellular signaling show increased NAD+ levels, along with Nampt activity involved in upregulating protective signaling in the diabetic heart. P7C3 has high therapeutic potential for rescuing heart disease.

NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.

The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.

Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators.

BACKGROUND: Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6-dibromo-α-[(phenylamino)methyl]-9H-carbazol-9-ethanol) ameliorates diabetes and muscle function. METHODS: We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt+/- mice were utilized to test the specificity of P7C3. RESULTS: Insulin resistance increased 1.6-fold in diabetic mice compared with wild-type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db-P7C3 mice fasting blood glucose levels decreased to 0.96-fold compared with C57Bl/6J wild-type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6-fold and 0.54-folds, respectively, at 120 min along with an increase in insulin secretion (1.76-fold) and pancreatic ß-cells (3.92-fold) in db-P7C3 mice. The fore-limb and hind-limb grip strengths were increased to 1.13-fold and 1.17-fold, respectively, together with a 14.2-fold increase in voluntary running wheel distance in db-P7C3 mice. P7C3 treatment resulted in a 1.4-fold and 7.1-fold increase in medium-sized and larger-sized myofibres cross-sectional area, with a concomitant 0.5-fold decrease in smaller-sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67-fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9-fold decrease in mitochondrial area in db-P7C3 mice compared with db-Veh mice. The number of SDH positive myofibres were increased to 1.74-fold in db-P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46-fold) and immunostaining (6.4-fold), respectively. qPCR analysis displayed a 2.9-fold and 1.3-fold increase in Pdk4 and Cpt1, and 0.55-fold and 0.59-fold decrease in Fgf21 and 16S in db-P7C3 mice. There was also a 3.3-fold and 1.9-fold increase in Fabp1 and CD36 in db-Veh mice. RNA-seq differential gene expression volcano plot displayed 1415 genes to be up-regulated and 1726 genes down-regulated (P < 0.05) in db-P7C3 mice. There was 1.02-fold increase in serum HDL, and 0.9-fold decrease in low-density lipoprotein/very low-density lipoprotein ratio in db-P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n-6; AA (0.83-fold), and n-3; DHA (0.69-fold) and EPA (0.81-fold), and a 0.66-fold decrease in endocannabinoid 2-AG and 2.0-fold increase in AEA in db-P7C3 mice. CONCLUSIONS: Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.

Deletion of Kvß2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes.

Kvß subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvß2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvß2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvß2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvß2 attenuated the QTc (corrected QT interval) prolongation at the electrocardiographic (ECG) level after a 14-day isoproterenol infusion, whereas the QTc was significantly prolonged in the littermate wildtype group. Monophasic action potentials verified the ECG changes, suggesting that cardiac changes and responses due to isoproterenol infusion are mediated similarly at both the in vivo and ex vivo levels. Moreover, the echocardiographic function showed no further decrease in the ejection fraction in the isoproterenol-stimulated Kvß2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvß2 plays a significant role in cardiovascular pathophysiology. Furthermore, the present study revealed SLC41a3, a major solute carrier transporter affected with a significantly decreased expression in KO vs. wildtype hearts. The electrical function showed that the decreased expression of SLC41a3 in Kvß2 KO hearts led to decreased Mg2+ responses, whereas, in the wildtype hearts, Mg2+ caused action potential duration (APD) shortening. Based on the in vivo, ex vivo, and molecular evaluations, we identified that the deletion of Kvß2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses.

PPARs and Microbiota in Skeletal Muscle Health and Wasting.

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often accompanied by chronic low-grade inflammation associated to inter- and intra-muscular fat deposition. During aging, muscle wasting is advanced due to increased movement disorders, as a result of restricted physical exercise, frailty, and the pain associated with arthritis. Muscle atrophy is characterized by increased protein degradation, where the ubiquitin-proteasomal and autophagy-lysosomal pathways, atrogenes, and growth factor signaling all play an important role. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of transcription factors, which are activated by fatty acids and their derivatives. PPARs regulate genes that are involved in development, metabolism, inflammation, and many cellular processes in different organs. PPARs are also expressed in muscle and exert pleiotropic specialized responses upon activation by their ligands. There are three PPAR isotypes, viz., PPARα, -ß/δ, and -γ. The expression of PPARα is high in tissues with effective fatty acid catabolism, including skeletal muscle. PPARß/δ is expressed more ubiquitously and is the predominant isotype in skeletal muscle. It is involved in energy metabolism, mitochondrial biogenesis, and fiber-type switching. The expression of PPARγ is high in adipocytes, but it is also implicated in lipid deposition in muscle and other organs. Collectively, all three PPAR isotypes have a major impact on muscle homeostasis either directly or indirectly. Furthermore, reciprocal interactions have been found between PPARs and the gut microbiota along the gut-muscle axis in both health and disease. Herein, we review functions of PPARs in skeletal muscle and their interaction with the gut microbiota in the context of muscle wasting.

Physical and Radiobiological Evaluation of Accelerated Intensity Modulated Radiotherapy for Locally Advanced Head and Neck Cancer and Comparison with Short-Term Clinical Outcomes.

Objective: The present study aims to evaluate the accelerated intensity modulated radiotherapy (IMRT) of head and neck (HandN) treatments using physical indices and radiobiological models with its clinical correlation using histogram analysis in radiation therapy (HART). The radiobiological evaluation in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP) indices were compared with acute toxicity. Materials and Methods: A total of twenty patients with stage III and IV of HandN cases treated with accelerated IMRT using 6MV photons were chosen for the study. Using HART software, physical indices of the IMRT plans have been defined by universal plan indices (UPI's) which summarize the various recognized plan indices. The overall quality factor (QF) of a plan was determined by a linear combination of all indices in UPI set. The clinical outcomes in terms of the acute toxicity like dysphagia and xerostomia were compared with NTCP values of the OAR calculated from HART software. Results: The mean QF and the mean Poisson TCP index was found to be 0.993±0.02 and 0.86 ±0.02 respectively. The mean JT Lyman NTCP index for bilateral parotid, constrictors, and larynx were found to be 0.23±0.14, 0.30±0.17 and 0.22±0.15 respectively. The acute toxicities in terms of severity of xerostomia and dysphagia have shown a moderate correlation with NTCP values of bilateral parotids, constrictors, and larynx, respectively. Conclusion: The mean QF based on UPI was found to be close to unity, which correlates with being a better IMRT plan. The present study suggested the existence of a moderate correlation between the calculated NTCP values and their respective severities of the organ at risk (OAR's). Accelerated IMRT with chemotherapy is a clinically feasible option in the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) with encouraging initial tumor response and acceptable acute toxicities.

Depletion of Gram-Positive Bacteria Impacts Hepatic Biological Functions During the Light Phase.

Living organisms display internal biological rhythms, which are an evolutionarily conserved adaptation to the environment that drives their rhythmic behavioral and physiological activities. The gut microbiota has been proposed, in association with diet, to regulate the intestinal peripheral clock. However, the effect of gut dysbiosis on liver remains elusive, despite that germfree mice show alterations in liver metabolic functions and the hepatic daily rhythm. We analyzed whether the disruption of gut microbial populations with various antibiotics would differentially impact liver functions in mice. Our results support the notion of an impact on the hepatic biological rhythm by gram-positive bacteria. In addition, we provide evidence for differential roles of gut microbiota spectra in xenobiotic metabolism that could protect against the harmful pharmacological effects of drugs. Our results underscore a possible link between liver cell proliferation and gram-positive bacteria.

Experimental Determination of Radial Dose Function and Anisotropy Function of GammaMed Plus 192Ir High-Dose-Rate Brachytherapy Source in a Bounded Water Phantom and its Comparison with egs_brachy Monte Carlo Simulation.

OBJECTIVE: The aim of the present study is to experimentally measure the radial dose function g(r) and anisotropy function F(r,θ) of GammaMed Plus 192Ir high-dose-rate source in a bounded water phantom using thermoluminescent dosimeter (TLD) and film dosimetry and compare the obtained results with egs_brachy Monte Carlo (MC)-calculated values for the same geometry. MATERIALS AND METHODS: The recently developed egs_brachy is a fast Electron Gamma Shower National Research Council of Canada MC application which is intended for brachytherapy applications. The dosimetric dataset recommended by Task Group 43 update (TG43U1) is calculated using egs_brachy for an unbounded phantom. Subsequently, radial dose function g(r) and anisotropy function F(r,θ) are measured experimentally in a bounded water phantom using TLD-100 and Gafchromic EBT2 film. RESULTS: The TG43U1 dosimetric parameters were determined using the egs_brachy MC calculation and compared with published data which are found to be in good agreement within 2%. The experimentally measured g(r) and F(r,θ) and its egs_brachy MC code-calculated values for a bounded phantom geometry are found to be good in agreement within the acceptable experimental uncertainties of 3%. CONCLUSION: Our experimental phantom size represents the average patient width of 30 cm; hence, results are closer to scattering conditions in clinical situations. The experimentally measured g(r) and F(r,θ) and egs_brachy MC calculations for bounded geometry are well in agreement within experimental uncertainties. Further, the confidence level of our comparative study is enhanced by validating the egs_brachy MC code for the unbounded phantom with respect to consensus data.

Evaluation of optically stimulated luminescence dosimeter for exit dose in vivo dosimetry in radiation therapy.

AIM: The aim of this study was to assess and analyze the exit dose in radiotherapy using optically stimulated luminescence dosimeter (OSLD) with therapeutic photon beams. MATERIALS AND METHODS: Measurements were carried out with OSLD to estimate the exit dose in phantom for different field sizes, various phantom thicknesses, and with added backscatter material. The data obtained were validated with ionization chamber data where applicable. A correction factor was found to determine the actual dose delivered at the exit surface using measured and theoretical dose. RESULTS: The exit dose factor with Co-60, 6 MV, and 18 MV beams for 10 cm phantom thickness was found to be 0.752 ± 0.38%, 0.808 ± 0.34%, and 0.882 ± 0.42%. The dose enhancement factor with field size was ranging from 3% to 7.7% for Co-60 beam, from 2.6% to 6.6% for 6 MV, and from 2.5% to 4.7% for 18 MV beams at 10 cm depth of the phantom with 20 cm backscatter. The percentage reduction in exit dose with no backscatter material at 25 cm depth with field size of 10 cm × 10 cm was 5.6%, 4.4%, and 4.0%, less than the dose with full backscatter thickness of 20 cm for Co-60 beam, 6 MV, and 18 MV beam. CONCLUSIONS: The promising results confirm that accurate in vivo exit dose measurements are possible with this potential dosimeter. This technique could be implemented as a part of quality assurance to achieve quality treatment in radiotherapy.

Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism.

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-ß, and E4BP4. PPARγ and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.

Dosimetric characterization of optically stimulated luminescence dosimeter with therapeutic photon beams for use in clinical radiotherapy measurements.

AIM: The modern radiotherapy techniques impose new challenges for dosimetry systems with high precision and accuracy in in vivo and in phantom dosimetric measurements. The knowledge of the basic characterization of a dosimetric system before patient dose verification is crucial. This incites the investigation of the potential use of nanoDot optically stimulated luminescence dosimeter (OSLD) for application in radiotherapy with therapeutic photon beams. MATERIALS AND METHODS: Measurements were carried out with nanoDot OSLDs to evaluate the dosimetric characteristics such as dose linearity, dependency on field size, dose rate, energy and source-to-surface distance (SSD), reproducibility, fading effect, reader stability, and signal depletion per read out with cobalt-60 (60 Co) beam, 6 and 18 MV therapeutic photon beams. The data acquired with OSLDs were validated with ionization chamber data where applicable. RESULTS: Good dose linearity was observed for doses up to 300 cGy and above which supralinear behavior. The standard uncertainty with field size observed was 1.10% ± 0.4%, 1.09% ± 0.34%, and 1.2% ± 0.26% for 6 MV, 18 MV, and 60 Co beam, respectively. The maximum difference with dose rate was 1.3% ± 0.4% for 6 MV and 1.4% ± 0.4% for 18 MV photon beams. The largest variation in SSD was 1.5% ± 1.2% for 60 Co, 1.5% ± 0.9% for 6 MV, and 1.5% ± 1.3% for 18 MV photon beams. The energy dependence of OSL response at 18 MV and 60 Co with 6 MV beam was 1.5% ± 0.7% and 1.7% ± 0.6%, respectively. In addition, good reproducibility, stability after the decay of transient signal, and predictable fading were observed. CONCLUSION: The results obtained in this study indicate the efficacy and suitability of nanoDot OSLD for dosimetric measurements in clinical radiotherapy.

Response of Nanodot Optically Stimulated Luminescence Dosimeters to Therapeutic Electron Beams.

Response of Al2O3:C-based nanoDot optically stimulated luminescence (OSL) dosimeter was studied for the dosimetry of 6, 9, 12, 16, and 20 MeV therapeutic electron beams. With reference to ionization chamber, no change in the response was observed with the change in the energy of electron beams for the field size from 6 cm × 6 cm to 25 cm × 25 cm, dose rates from 100 MU/min to 600 MU/min, and the linearity in the response up to 300 cGy. The fading of the transient signal was higher for 20 MeV electron beam than that of 6 MeV electron beam by about 5% as compared to value at 20 min after irradiation. The depletion of OSL signal per readout in 200 successive readouts was also found to change with dose and energy of electron beam from 6 MeV (9% and 12% per readout at 2 and 10 Gy, respectively) to 20 MeV (9% and 16% at 2 and 10 Gy, respectively). The OSL sensitivity changed in the range from 2% to 6% with accumulated doses from 2 to 8 Gy and with electron energy from 6 to 20 MeV, but the sensitivity could be reset using an optical annealing treatment. Although negligible fading for postirradiation storage from 20 min to several months, acceptable precision and linearity in the desired range, and high reproducibility makes nanoDot dosimeters very attractive for the dosimetry of therapeutic electron beams, a note should be made for changes in sensitivity at doses beyond 2 Gy and electron beams energy dependence in reuse, short-term fading, and signal depletion on repeated readout.

Roles of Peroxisome Proliferator-Activated Receptor ß/δ in skeletal muscle physiology.

More than two decades of studying Peroxisome Proliferator-Activated Receptors (PPARs) has led to an understanding of their implications in various physiological processes that are key for health and disease. All three PPAR isotypes, PPARα, PPARß/δ, and PPARγ, are activated by a variety of molecules, including fatty acids, eicosanoids and phospholipids, and regulate a spectrum of genes involved in development, lipid and carbohydrate metabolism, inflammation, and proliferation and differentiation of many cell types in different tissues. The hypolipidemic and antidiabetic functions of PPARα and PPARγ in response to fibrate and thiazolidinedione treatment, respectively, are well documented. However, until more recently the functions of PPARß/δ were less well defined, but are now becoming more recognized in fatty acid metabolism, energy expenditure, and tissue repair. Skeletal muscle is an active metabolic organ with high plasticity for adaptive responses to varying conditions such as fasting or physical exercise. It is the major site of energy expenditure resulting from lipid and glucose catabolism. Here, we review the multifaceted roles of PPARß/δ in skeletal muscle physiology.

The effect of influence quantities and detector orientation on small-field patient-specific IMRT QA: comparison of measurements with various ionization chambers.

Intensity-modulated radiation therapy (IMRT) requires a patient-specific quality assurance (QA) program to validate the treatment plan and a high level of dosimetric accuracy in the treatment delivery. Dosimetric verification generally consists of both absolute- and relative-dose measurements in a phantom using ionization chambers. Measurements were carried out with three different ionization chambers (Scanditronix FC 65G, Exradin A18, and PTW PinPoint 31014) to assess the effects of influence quantities such as the stability, pre- and post-irradiation leakage, stem effect, polarity, and ion recombination on the IMRT point-dose verification with two different orientations. The Exradin A18 and PTW PinPoint ion chambers demonstrated noticeable leakage to magnitudes of 0.6 and 1.2%, whereas negligible leakage was observed with FC 65G ion chamber. Maximum deviations of 0.5 and 0.6% were noticed for the smallest field owing to the ion recombination effect with the PTW PinPoint ion chamber in the parallel and perpendicular orientations, respectively. The calculated total uncertainties of all influence quantities for the FC 65G, A18, and PTW PinPoint ion chambers were 0.5, 0.7, and 1.3%, respectively. The uncertainties determined for each chamber were incorporated into the point-dose measurements of 30 head and neck patient-specific QA plans, and the variation was found to be within ±3%. The magnitude of the leakage in a small-volume ion chamber indicated the significance of incorporating the correction factors in the absolute-dose measurement. A paired t test analysis indicated that the influence quantities significantly affect the point-dose measurements in the patient-specific IMRT QA.

Dosimetric evaluation of newly developed well-type ionization chamber for use in the calibration of brachytherapy sources.

The well-type ionization chamber has been designed for convenient use in brachytherapy source strength calibration. The chamber has a volume of 240 cm3, weight of 2.5 kg, and is open to atmospheric conditions. The well-type ionization chamber dosimetric characteristics such as leakage current, stability, scattering effect, ion collection efficiency, and nominal response with energy were studied. The evaluated dosimetric characteristics of well-type ionization chamber were compared with two other commercially available well-type ionization chambers. The study shows that the newly developed well-type ionization chamber is reliable for air-kerma strength calibration. The results obtained confirm that this chamber can be used for the calibrations of high-dose rate brachytherapy sources.