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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 antioxidant 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 (NAMPT) 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.

Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD

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.

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.

Kvβ 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 Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 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 Kvβ2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvβ2 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 Kvβ2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvβ2 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 Kvβ2 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 Kvβ2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses.

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.

Dose measurement with ionization chamber is essential to deliver accurate dose to the tumor in radiotherapy. The cylindrical Farmer-type ionization chamber is recommended by various dosimetry protocols for dose measurement of radiotherapy beams. The air-equivalent graphite wall Farmer-type ionization chamber (FAR 65 GB) of active volume 0.65 cm3 with aluminum as the central electrode material was fabricated. Various dosimetric parameters were studied for the newly developed ionization chamber in cobalt-60, 6 and 18 MV photon beams. The preirradiation and postirradiation leakage of the chamber was within 0.08%. The long-term stability and the stem effect of the chamber were within 0.07% and 0.3%, respectively. The sensitivity of the ionization chamber was found to be 22.15 nC/Gy. The chamber shows linear response with dose for cobalt-60, 6 and 18 MV photon beams. The ion recombination correction factor increases with increase in bias voltage. For all energies and field sizes, the polarity correction factor is almost closer to unity. The ion recombination and polarity correction measurements show that the polarizing potential and polarity recommended during the calibration of ionization chamber should be used for routine measurement to avoid the uncertainty. The chamber response is independent of dose rate and energy. The chamber is cost-effective and shows precise and reproducible response. The study carried out confirms that the newly fabricated ion chamber can be used in the measurement of absolute dose for high-energy photon beams.

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.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.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.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.

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 - β , 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.

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.

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.

AimTo compare the measured and calculated individual and composite field planar dose distribution of Intensity Modulated Radiotherapy plans.Materials and methodsThe measurements were performed in Clinac DHX linear accelerator with 6MV photons using Matrixx device and a solid water phantom. The 20 brain tumor patients were selected for this study. The IMRT plan was carried out for all the patients using Eclipse treatment planning system. The verification plan was produced for every original plan using CT scan of Matrixx embedded in the phantom. Every verification field was measured by the Matrixx. The TPS calculated and measured dose distributions were compared for individual and composite fields.Results and discussionThe percentage of gamma pixel match for the dose distribution patterns were evaluated using gamma histogram. The gamma pixel match was 95–98% for 41 fields (39%) and 98% for 59 fields (61%) with individual fields. The percentage of gamma pixel match was 95–98% for 5 patients and 98% for other 12 patients with composite fields. Three patients showed a gamma pixel match of less than 95%. The comparison of percentage gamma pixel match for individual and composite fields showed more than 2.5% variation for 6 patients, more than 1% variation for 4 patients, while the remaining 10 patients showed less than 1% variation.ConclusionThe individual and composite field measurements showed good agreement with TPS calculated dose distribution for the studied patients. The measurement and data analysis for individual fields is a time consuming process, the composite field analysis may be sufficient enough for smaller field dose distribution analysis with array detectors.

Activation of the aryl hydrocarbon receptor (AHR), an environment-sensing transcription factor, causes profound impairment of mammary gland differentiation during pregnancy. Defects include decreased ductal branching, poorly formed alveolar structures, suppressed expression of milk proteins, and failure to nutritionally support offspring. AHR is activated by numerous environmental toxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and plays an as yet poorly understood role in development and reproduction. To better understand how AHR activation affects pregnancy-associated mammary gland differentiation, we used a combination of ex vivo differentiation, mammary epithelial transplantation, and AHR-deficient mice to determine whether AHR modulates mammary development through a direct effect on mammary epithelial cells (MECs) or by altering paracrine or systemic factors that drive pregnancy-associated differentiation. Studies using mutant mice that express an AHR protein lacking the DNA-binding domain show that defects in pregnancy-associated differentiation require AHR:DNA interactions. We then used fluorescence-based cell sorting to compare changes in gene expression in MECs and whole mammary tissue to gain insight into affected signaling pathways. Our data indicate that activation of the AHR during pregnancy directly affects mammary tissue development via both a direct effect on MECs and through changes in cells of the fat pad, and point to gene targets in MECs and stromal tissues as putative AHR targets.

For intensity‐modulated radiation therapy, evaluation of the measured dose against the treatment planning calculated dose is essential in the context of patient‐specific quality assurance. The complexity of volumetric arc radiotherapy delivery attributed to its dynamic and synchronization nature require new methods and potentially new tools for the quality assurance of such techniques. In the present study, we evaluated and compared the dosimetric performance of EDR2 film and three other commercially available quality assurance devices: IBA I'MatriXX array, PTW Seven29 array and the Delta 4 array. The evaluation of these dosimetric systems was performed for RapidArc and IMRT deliveries using a Varian NovalisTX linear accelerator. The plans were generated using the Varian Eclipse treatment planning system. Our results showed that all four QA techniques yield equivalent results. All patient QAs passed our institutional clinical criteria of gamma index based on a 3% dose difference and 3 mm distance to agreement. In addition, the Bland‐Altman analysis was performed which showed that all the calculated gamma values of all three QA devices were within 5% from those of the film. The results showed that the four QA systems used in this patient‐specific IMRT QA analysis are equivalent. We concluded that the dosimetric systems under investigation can be used interchangeably for routine patient specific QA. PACS numbers: 87.55.Qr, 87.56.Fc

The complexity of VMAT delivery requires new methods and potentially new tools for the commissioning of these systems. It appears that great consideration is needed for quality assurance (QA) of these treatments since there are limited devices that are dedicated to the QA of rotational delivery. In this present study, we have evaluated the consistency and reproducibility of one prostate and one lung VMAT plans for 31 consecutive days using three different approaches: 1) MLC DynaLog files, 2) in vivo measurements using the multiwire ionization chamber DAVID, and 3) using PTWseven29 2D ARRAY with the OCTAVIUS phantom at our Varian Clinac linear accelerator. Overall, the three methods of testing the reproducibility and consistency of the VMAT delivery were in agreement with each other. All methods showed minimal daily deviations that contributed to clinically insignificant dose variations from day to day. Based on our results, we conclude that the VMAT delivery using a Varian 2100CD linear accelerator equipped with 120 MLC is highly reproducible. PACS numbers: 87.55.Qr and 87.56.Fc

Intensity‐modulated radiotherapy treatment demands stringent quality assurance and accurate dose determination for delivery of highly conformal dose to the patients. Generally 3D dose distributions obtained from a treatment planning system have to be verified by dosimetric methods. Mainly, a comparison of two‐dimensional calculated and measured data in several coplanar planes is performed. In principle, there are many possibilities to measure two‐dimensional dose distributions such as films, flat‐panel electronic portal imaging devices (EPID), ion chambers and ionization chamber arrays, and radiographic and radiochromic films. The flat‐panel EPIDs show a good resolution and offer a possibility for real‐time measurements: however to convert the signal into dose, a separate commercial algorithm is required. The 2D ion chamber array system offers the real‐time measurements. In this study, dosimetric characteristics of 2D ion chamber array matrix were analyzed for verification of radiotherapy treatments. The dose linearity and dose rate effect of the I'matriXX device was studied using 6 MV, 18 MV photons and 12 MeV electrons. The output factor was estimated using I'matriXX device and compared with ion chamber measurements. The ion chamber array system was found to be linear in the dose range of 2–500 cGy and the response of the detector was found to be independent of dose rate between 100 MU/min to 600 MU/min. The estimated relative output factor with I'matriXX was found to match very well with the ion chamber measurements. To check the final dose delivered during IMRT planning, dose distribution patterns such as field‐in‐field, pyramidal, and chair tests were generated with the treatment planning system (TPS) and the same was executed in the accelerator and measured with the I'matriXX device. The dose distribution pattern measured by the matrix device for field‐in‐field, pyramidal, and chair test were found to be in good agreement with the calculated dose distribution by TPS both for 6 and 18 MV photons (γ ≤ 1: 96%, criteria 3%, 3 mm). Two 7‐field IMRT plans (one prostate, one head and neck) dose distribution patterns were also measured with I'matriXX device and compared with film dosimetry. The measurements and evaluation proves that I'matriXX can be used for quantifying absolute dose. Moreover, using I'matriXX as absolute dosimeter in IMRT field verification, avoids the time‐consuming procedure of making ionometric measurement for absolute dose estimation and film for dose distribution verification. The I'matriXX can also used for routine quality assurance checks like flatness, symmetry, field width, and penumbra of the linear accelerator beam. PACS number: 87.55.ne and 87.56.Fc

Peroxisome proliferator-activated receptor β/δ ( PPARβ/δ) is a ubiquitously expressed gene with higher levels observed in skeletal muscle. Recently, our laboratory showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that PPARβ/δ modulates myostatin activity to induce myogenesis in skeletal muscle. In the present study, we show that PPARβ/δ-null mice display reduced body weight, skeletal muscle weight, and myofiber atrophy during postnatal development. In addition, a significant reduction in satellite cell number was observed in PPARβ/δ-null mice, suggesting a role for PPARβ/δ in muscle regeneration. To investigate this, tibialis anterior muscles were injured with notexin, and muscle regeneration was monitored on days 3, 5, 7, and 28 postinjury. Immunohistochemical analysis revealed an increased inflammatory response and reduced myoblast proliferation in regenerating muscle from PPARβ/δ-null mice. Histological analysis confirmed that the regenerated muscle fibers of PPARβ/δ-null mice maintained an atrophy phenotype with reduced numbers of centrally placed nuclei. Even though satellite cell numbers were reduced before injury, satellite cell self-renewal was found to be unaffected in PPARβ/δ-null mice after regeneration. Previously, our laboratory had showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that inactivation of PPARβ/δ increases myostatin signaling and inhibits myogenesis. Our results here indeed confirm that inactivation of myostatin signaling rescues the atrophy phenotype and improves muscle fiber cross-sectional area in both uninjured and regenerated tibialis anterior muscle from PPARβ/δ-null mice. Taken together, these data suggest that absence of PPARβ/δ leads to loss of satellite cells, impaired skeletal muscle regeneration, and postnatal myogenesis. Furthermore, our results also demonstrate that functional antagonism of myostatin has utility in rescuing these effects.

Growth factors, such as myostatin (Mstn), play an important role in regulating post-natal myogenesis. In fact, loss of Mstn has been shown to result in increased post-natal muscle growth through enhanced satellite cell functionality; while elevated levels of Mstn result in dramatic skeletal muscle wasting through a mechanism involving reduced protein synthesis and increased ubiquitin-mediated protein degradation. Here we show that miR-27a/b plays an important role in feed back auto-regulation of Mstn and thus regulation of post-natal myogenesis. Sequence analysis of Mstn 3′ UTR showed a single highly conserved miR-27a/b binding site and increased expression of miR-27a/b was correlated with decreased expression of Mstn and vice versa both in vitro and in mice in vivo. Moreover, we also show that Mstn gene expression was regulated by miR-27a/b. Treatment with miR-27a/b-specific AntagomiRs resulted in increased Mstn expression, reduced myoblast proliferation, impaired satellite cell activation and induction of skeletal muscle atrophy that was rescued upon either blockade of, or complete absence of, Mstn. Consistent with this, miR-27a over expression resulted in reduced Mstn expression, skeletal muscle hypertrophy and an increase in the number of activated satellite cells, all features consistent with impaired Mstn function. Loss of Smad3 was associated with increased levels of Mstn, concomitant with decreased miR-27a/b expression, which is consistent with impaired satellite cell function and muscular atrophy previously reported in Smad3-null mice. Interestingly, treatment with Mstn resulted in increased miR-27a/b expression, which was shown to be dependent on the activity of Smad3. These data highlight a novel auto-regulatory mechanism in which Mstn, via Smad3 signaling, regulates miR-27a/b and in turn its own expression. In support, Mstn-mediated inhibition of Mstn 3′ UTR reporter activity was reversed upon miR-27a/b-specific AntagomiR transfection. Therefore, miR-27a/b, through negatively regulating Mstn, plays a role in promoting satellite cell activation, myoblast proliferation and preventing muscle wasting. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version

Purpose: To evaluate the dosimetric characteristics of newly developed well type ionization chamber and to validate the results with the commercially available calibrated well chambers that are being used for the calibration of brachytherapy sources. Methods: The newly developed well type ionization chamber (BDS 1000) has been designed for the convenient use in brachytherapy which is open to atmospheric condition. The chamber has a volume of 240 cm3 and weight of 2.5 Kg. The calibration of the radioactive source with activities from 0.01 mCi to 20 Ci can be carried out using this chamber. The dosimetric parameters such as leakage current, stability, scattering effect, ion collection efficiency, reference air kerma rate and nominal response with energy were carried out with the BDS 1000 well type ion chamber. The evaluated dosimetric characteristics of BDS1000 well chamber were validated with two other commercially available well chambers (HDR 1000 plus and BTC/3007). Results: The measured leakage current observed was negligible for the newly developed BDS 1000 well type ion chamber. The ion collection efficiency was close to 1 and the response of the chamber was found to be very stable. The determined sweet spot was at 42 mm from bottom of the chamber insert. The reference air kerma rate was found to be 4.634 × 105 Gym2hr-1A-1 for the BDS 1000 well chamber. The overall dosimetric characteristics of BDS 1000 well chamber was in good agreement with the dosimetric properties of other two well chambers. Conclusion: The dosimetric study shows that the newly developed BDS 1000 well type ionization chamber is high sensitive and reliable chamber for reference air kerma strength calibration. The results obtained confirm that this chamber can be used for the calibration of HDR and LDR brachytherapy sources.

In order to verify intensity modulated radiotherapy quality assurance procedure and to establish the practical base line commissioning, American Association of Physicists in Medicine-Task Group 119 test suite DICOM-RT images and structure were downloaded for planning and dosimetric comparison. The square slab phantom of water equivalent plastic was used for the measurement. This phantom can permit point dose measurement with ionization chamber by placing the chamber at 7.5 cm depth in the slab phantom. The planar dose measurements were carried out by positioning the Matrixx detector at 10 cm depth. The planning and measurements were performed as per AAPM TG119 guidelines. The test suite includes AP:PA field, band test, multitarget, prostate, head and neck and C-shape. The ion chamber measurements were within 3% of the planned dose for target and avoidance structure region. The ion chamber measurement results are in good agreement with the TG119 recommendation of ±3% for all the test suites. The planar dose measurements were performed with Matrixx for individual fields at the planned gantry angle. The results show that the pass criteria for γ ≤ 1 were between 93 to 97% for all the test cases. Our results are in good agreement with the TG119 recommendation. The present study aimed to compare the measured dose with the planned dose using computer planning system. The test suites were used to assess the planning and delivery systems so as to provide the basis for IMRT commissioning and QA.

IMRT implementation and patient specific dose verification with film and ion chamber array detectors Implementation of Intensity Modulation Radiotherapy (IMRT) and patient dose verification was carried out with film and I'mariXX using linear accelerator with 120-leaf Millennium dynamic multileaf collimator (dMLC). The basic mechanical and electrical commissioning and quality assurance tests of linear accelerator were carried out. The leaf position accuracy and leaf position repeatability checks were performed for static MLC positions. Picket fence test and garden fence test were performed to check the stability of the dMLC and the reproducibility of the gap between leaves. The radiation checks were performed to verify the position accuracy of MLCs in the collimator system. The dMLC dosimetric checks like output stability, average leaf transmission and dosimetric leaf separation were also investigated. The variation of output with gravitation at different gantry angles was found to be within 0.9%. The measured average leaf transmission for 6 MV was 1.6% and 1.8% for 18 MV beam. The dosimetric leaf separation was found to be 2.2 mm and 2.3 mm for 6 MV and 18 MV beams. In order to check the consistency of the stability and the precision of the dMLC, it is necessary to carryout regular weekly and monthly checks. The dynalog files analysis for Garden fence, leaf gap width and step wedge test patterns carried out weekly were in good agreement. Pretreatment verification was performed for 50 patients with ion chamber and I'matiXX device. The variations of calculated absolute dose for all treatment fields with the ion chamber measurement were within the acceptable criterion. Treatment Planning System (TPS) calculated dose distribution pattern was comparable with the I'matriXX measured dose distribution pattern. Out of 50 patients for which the comparison was made, 36 patients were agreed with the gamma pixel match of > 95% and 14 patients were with the gamma pixel match of 90-95% with the criteria of 3% delta dose (DD) and 3 mm distance-to-agreement (DTA). Commissioning and quality assurance of dMLC for IMRT application requires considerable time and effort. Many dosimetric characteristics need to be assessed carefully failing which the delivered dose will be significantly different from the planned dose. In addition to the issues discussed above we feel that individual MU check is necessary before the treatment is delivered.

GDF-8 is recognised as an inhibitor of muscle cell growth and differentiation. Although initially thought to be restricted to muscle cells it is now accepted that GDF-8 expression has a broader tissue distribution. We demonstrate GDF-8 expression in the mouse mammary gland, which is predominantly associated with epithelial cells and displays an inverse correlation to the differentiated state of the gland. Specifically, the highest GDF-8 mRNA levels correlate with periods of maximal ductal growth, diminish as pregnancy progressed and are down-regulated to minimal levels by the onset of lactation as the epithelium differentiates. A similar profile is observed for both GDF-8 protein processing and reflects Smad2/3 phosphorylation profile. However, in contrast to muscle cells, GDF-8 neither reduces proliferation nor induces p21 expression levels in mammary epithelial cells. These data implicate a role for GDF-8 in mammary epithelial cell differentiation and demonstrate that GDF-8 has cell-type specific activities. Mol. Reprod. Dev. 75: 1783–1788, 2008. © 2008 Wiley-Liss, Inc.

Purpose: The aim of this study was to compare few of the dosimetric characteristics of a physical and enhanced dynamic wedge from a dual energy (6 and 18 MV) linear accelerator.Materials and Methods: This study used the Varian Clinac‐DHX (S.No.3172) linear accelerator which is equipped with three different type of wedges. To compare the change in beam quality with physical and enhanced dynamic wedge half value layer (HVL) was measured using a 0.14 cc ion chamber covered with brass build up cap positioned at 2 meter distance from the source and the distance from the target to absorber distance was maintained as 1 meter. Transmission measurements were made for varying thickness of white polystyrene phantom placed on the couch. The surface dose with physical and enhanced dynamic wedges were measured using a parallel plate chamber at 85 and 100 cm source to surface distance (SSD), for 6 and 18 MV photons.Results: The HVL was estimated for 6 and 18 MV photons along the central axis and at off‐axis points for the field size of 20 × 20 cm2 with 45° upper physical wedge and compared with that of the enhanced dynamic wedge (EDW). For physical wedged field, at heel edge side HVL value was high compared with the measured that of EDW. It was noticed that, the HVL variation across the beam was significantly high for 6 MV X‐rays than for 18 MV X‐rays. The measured surface dose was found to be more at 85 cm FSD for all the fields. The lower energy photons (6 MV) were found to result in higher surface dose than the higher energy photons (18 MV). Conclusion: The three wedge systems produce significantly different surface doses that should be considered in properly choosing a wedge system for clinical use.

Purpose: To analyze the treatment plans generated using physical and enhanced dynamic wedges for head and neck patients from Eclipse treatment planning system. Materials and Methods: The physical wedge filters of angles of 15°, 30°, 45° and 60° are used. In Enhanced Dynamic Wedge technique no external beam modifier is used to create wedge dose profiles, instead wedged isodose profiles is created by the sweeping action of the jaw from open to closed position while the beam is on. The dose rate and jaw speed are also varied during the treatment, which is the function of selected energy, field size and wedge angle. The single STT called Golden STT (GSTT) is used for 60° wedge angle and other wedge effects are obtained by mixing open and wedge field intensities. The conformal treatment plans of 20 head and neck patients were used in this study. Plans are generated using both physical and enhanced dynamic wedges. The dose was normalized to 100% at isocenter. The plans were compared using Dose‐Volume histogram (DVH) tool. Results and Discussion: The treatment plans generated shows that the enhanced dynamic wedge plans were comparable with that of the physical wedge plan and the DVH analysis showed that the critical organ sparing is slightly better with enhanced dynamic wedge. The maximum dose within the target volume is higher in physical wedge plan. The number of monitor units to deliver a particular dose with EDW field is less than that of PW field due to change in wedge factor, which could probably reduce the scatter dose to structures off the field. Enhanced dynamic wedges eliminate the beam hardening effect, and also it is possible to obtain an asymmetric wedge fields with EDW. The dose and jaw position control accuracy statistics are displayed and saved to dynalog files after treatment.

Purpose: The aim of this study was to dosimetrically evaluate various intraluminal brachytherapy applicators for the Gammamed high dose rate afterloading system. Materials and methods:Dosimetric evaluation was carried out for 8 mm, 10 mm, 12 mm and 14 mm diameter intraluminal applicators available with the Gammamed high dose rate afterloading system. Treatment planning for these applicators was carried out with abacus treatment planning system for active source length and 8 cm, 10 cm and 12 cm. All evaluations were carried out for prescription dose of 5 Gy at the reference point of 1cm from source axis. Reference volume length (RVL), Treated volume (TV), Hyper dose sleeve radius (HSR) were noted down from the isodose plans. Iterative, geometric and equal times optimization routines were carried out for all evaluations with step size of 0.5cm. Results: The isodose curves showed tapering pattern towards the distal and proximal regions. The reference volume lengths were larger than active source lengths for 8mm and 10mm diameter applicators. Reference volume lengths were smaller than active source length for 12mm and 14mm diameter applicators hyper dose sleeve radius decreases with increase in diameter of the applicator. For 14mm diameter applicators, the hyper dose sleeve radius was smaller than the radius of the reference isodose. Iterative optimization routine gave better average in terms of reference volume length few are four diameter applicators. Conclusions: We evaluated the dosimetric parameters for various intraluminal applicators available with the Gamma med high dose rate remote after loading system. The values of RVL and HSR were within acceptable limits for the four applicators considered in this study.

Purpose: The aim of this study was to optimize dose distribution for Gammamed plus vaginal cylinders and the placement of dose optimization points was evaluated for its effect on optimized dose distributions. Materials and methods: The HDR source travels through the central tandem, distal to proximal, stopping at dwell positions defined by step sizes. Two different dose optimization point models were used in this study namely, non apex (dose optimization points only on periphery) and apex (dose optimization points on periphery and along the curvature including the apex points). Thirteen dwell positions were used for the HDR dosimetry to obtain a 6 cm active length. Diameters of vaginal cylinders varied from 2.0 to 4.0 cm. Iterative optimization routine was utilized for all optimizations. The effects of various optimization routines (iterative, geometric, equal times) was studied for the 3.0 cm diameter vaginal cylinder. The effect of source travel step size on the optimized dose distributions for vaginal cylinders was also evaluated. Results: For both non‐apex and apex models of vaginal cylinders, doses for apex point and three dome points were higher for apex model compared to non‐apex model. Mean doses to the optimization points for both the cylinder models and all the cylinder diameters were 6 Gy matching with the prescription dose of 6.00 Gy. Iterative optimization routine resulted in the highest dose to apex point and dome points. The mean dose for optimization point was 6.01 Gy for iterative optimization and was much higher than 5.74 Gy for geometric and equal times routines. Conclusion: In our study best doses were obtained for the optimization points for 1 cm step size and iterative optimization routine for the apex model vaginal cylinder. Selection of dose optimization points for the derivation of optimized dose distributions for vaginal cylinders affects the dose distributions.