The response of the 2D detector array, MP512, has been evaluated. The properties of the array demonstrated suitability for use as in phantom dosimeter for QA in SRS and SBRT. Although MP512 matches film measurements down to 1×1 cm2 well, it showed a discrepancy of 4% in the determination of output factors of beams smaller than 0.5×0.5 cm2 due to the field perturbation generated by the large amount of silicon surrounding the central diode. MP512 is highly capable of measuring beam size (FWHM) and has a discrepancy of less than 1.3% when compared to EBT3 film. A reduction in the detector pitch to less than 2 mm would improve the penumbra reconstruction accuracy at the cost readout electronics complexity.

Background and objective: With the worldwide emergence of highly drug-resistant tuberculosis (TB), novel agents that have direct antimycobacterial effects or that enhance host immunity are urgently needed. Curcumin is a polyphenol responsible for the bright yellow-orange colour of turmeric, a spice derived from the root of the perennial herb Curcuma longa. Curcumin is a potent inducer of apoptosis-an effector mechanism used by macrophages to kill intracellular Mycobacterium tuberculosis (MTB). Methods: An in vitro human macrophage infection model was used to determine the effects of curcumin on MTB survival. Results: We found that curcumin enhanced the clearance of MTB in differentiated THP-1 human monocytes and in primary human alveolar macrophages. We also found that curcumin was an inducer of caspase-3-dependent apoptosis and autophagy. Curcumin mediated these anti-MTB cellular functions, in part, via inhibition of nuclear factor-kappa B (NFκB) activation. Conclusion: Curcumin protects against MTB infection in human macrophages. The host-protective role of curcumin against MTB in macrophages needs confirmation in an animal model; if validated, the immunomodulatory anti-TB effects of curcumin would be less prone to drug resistance development.

Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively “glues” cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our results describe a new role for Dex as a suppressor of GBM dispersal and growth.

We combine mechanical rheometry, DWS, and SANS with a simulation model, the “pointer algorithm”, to obtain characteristic lengths and time constants for WLM solutions over a range of salt concentrations encompassing the transition from unentangled to entangled solutions.

Interleukin 4 (IL-4) is secreted by activated T cells and pleiotropically modulates both B-and T-lymphocyte function. In murine helper (CD4+) T-cell clones IL-4 production appears to be regulated independently of interferon Y and interleukin 2. To determine whether production of these lymphokines is also differentially regulated in uncloned human T cells, we studied lymphokine production *iy normal human peripheral T cells and T-cell subsets after ii vitro polyclonal activation. After maximal induction of lymphokine expression, IL-4 mRNA was detectable in <5% of CD41 and 1-2% of unfractionated T cells, whereas '33% and 60% of CD4' cells expressed detectable mRNA for interferon y and interleukin 2, respectively. This finding correlated with dramatically lower production of IL-4 mRNA and protein than of interferon rand interleukin 2 by peripheral blood and tonsillar T cells. The helper-inducer (CD4' CD45R-) T-cell subset, which significantly enhances in vitro immunoglobulin production, accounted for the preponderance of IL-4 mRNA accumulation and protein production by CD41 T cells; nevertheless, cells with detectable IL-4 mRNA constituted <10% of the CD4' CD45R-subset. Limitation of IL-4 production to a comparatively small population of normal human T cells could selectively regulate the effects of this lymphokine in T-cell-mediated immune responses; such selective regulation may be a fundamental mechanism for restricting the potentially pleiotropic effects of certain tymphokines to appropriate responder cells.Interleukin 4 (IL-4) is a T-cell lymphokine that modulates lymphocyte function by promoting B-cell growth, regulating immunoglobulin isotype expression, and promoting T-cell growth and cytotoxicity (1)(2)(3)(4). Interferon y (IFN-'y) (5,6) and, to a lesser extent, interleukin 2 (IL-2) (6, 7), which are primarily produced by activated T cells, also have pleiotropic effects on lymphoid cells. In certain cases all three lymphokines may have similar or synergistic activities, such as the enhancement of T-cell-mediated cytotoxicity (4,8), whereas in other situations, such as the regulation of immunoglobulin isotype expression by IL-4 and IFN-y, differential or antagonistic effects have been demonstrated (2, 9, 10).These in vitro findings raise the question as to how lymphokine production by activated T cells is regulated in vivo to result in an integrated effective immune response. One mechanism to facilitate distinct T-cell effector functions would be to limit the production of a lymphokine to a particular subtype ofT cells. Such segregation ofCD4' T-cell lymphokine production has been proposed by Mosmann and co-workers (11, 12) from the observation that most murine CD4' clones produce either IL-4 or IFN-y and IL-2 in a mutually exclusive fashion. However, most human CD4' T-cell clones do not appear to conform to this pattern (9, 13), and there is evidence that the patterns of lymphokine production obtained in clones may be influenced by the conditions used during the cloning process (14). In addition, c...

Background The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single nucleotide polymorphism (SNP) in EC-SOD (rs1799895) leads to an arginine to glycine (Arg->Gly) amino acid substitution at position 213 (R213G) in the heparin-binding domain (HBD). In recent human genetic association studies, this SNP attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease. Methods and Results Capitalizing on the complete sequence homology between human and mouse in the HBD, we created an analogous R213G SNP knockin mouse. The R213G SNP did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (e.g. bronchoalveolar lavage fluid (BALF) and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension). Conclusions We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.

Mycobacterium abscessus (M. abscessus) infections, particularly those causing chronic lung diseases, are becoming more prevalent worldwide. M. abscessus infections are difficult to treat due to antibiotic resistance. Thus, new treatment options are urgently needed. M. abscessus are intracellular pathogens that primarily infect macrophages and fibroblasts. Because this bacterium has only recently been identified as a separate species, very little is known about M. abscessus-host interactions and how M. abscessus growth is regulated. Oxidative stress has long been shown to inhibit growth of bacterial organisms. However, some intracellular bacteria, such as Mycobacterium tuberculosis, grow well in oxidizing environments. In the present study, we show that M. abscessus infection causes the host cell environment to become more oxidizing. Furthermore, we show that a more oxidizing environment leads to enhanced growth of M. abscessus inside macrophages. In the presence of the antioxidants, MnTE-2-PyP (chemical name: Manganese (II) Meso-Tetrakis-(N-Methylpyridinium-2-yl) porphryin) or N-acetyl-L-cysteine (NAC), M. abscessus growth is inhibited. These results lead us to postulate that antioxidants may aid in the treatment for M. abscessus infections.

To improve radiation therapy-induced quality of life impairments for prostate cancer patients, the development of radio-protectors is needed. Our previous work has demonstrated that MnTE-2-PyP significantly protects urogenital tissues from radiation-induced damage. So, in order for MnTE-2-PyP to be used clinically as a radio-protector, it is fully necessary to explore the effect of MnTE-2-PyP on human prostate cancer progression. MnTE-2-PyP inhibited prostate cancer growth in the presence and absence of radiation and also inhibited prostate cancer migration and invasion. MnTE-2-PyP altered p300 DNA binding, which resulted in the inhibition of HIF-1β and CREB signaling pathways. Accordingly, we also found that MnTE-2-PyP reduced the expression of three genes regulated by HIF-1β and/or CREB: TGF-β2, FGF-1 and PAI-1. Specifically, MnTE-2-PyP decreased p300 complex binding to a specific HRE motif within the PAI-1 gene promoter region, suppressed H3K9 acetylation, and consequently, repressed PAI-1 expression. Mechanistically, less p300 transcriptional complex binding is not due to the reduction of binding between p300 and HIF-1/CREB transcription factors, but through inhibiting the binding of HIF-1/CREB transcription factors to DNA. Our data provide an in depth mechanism by which MnTE-2-PyP reduces prostate cancer growth and metastasis, which validates the clinical use of MnTE-2-PyP as a radio-protector to enhance treatment outcomes in prostate cancer radiotherapy.