Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo

AbstractHigher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy

Immunization against Leishmania major Infection Using LACK- and IL-12-Expressing Lactococcus lactis Induces Delay in Footpad Swelling

BACKGROUND: Leishmania is a mammalian parasite affecting over 12 million individuals worldwide. Current treatments are expensive, cause severe side effects, and emerging drug resistance has been reported. Vaccination is the most cost-effective means to control infectious disease but currently there is no vaccine available against Leishmaniasis. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used to express biologically active molecules including vaccine antigens and cytokines. METHODOLOGY/PRINCIPAL FINDINGS: We report the generation of L. lactis strains expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall. L. lactis was also engineered to secrete biologically active single chain mouse IL-12. Subcutaneous immunization with live L. lactis expressing LACK anchored to the cell wall and L. lactis secreting IL-12 significantly delayed footpad swelling in Leishmania major infected BALB/c mice. The delay in footpad swelling correlated with a significant reduction of parasite burden in immunized animals compared to control groups. Immunization with these two L. lactis strains induced antigen-specific multifunctional T(H)1 CD4(+) and CD8(+) T cells and a systemic LACK-specific T(H)1 immune response. Further, protection in immunized animals correlated with a Leishmania-specific T(H)1 immune response post-challenge. L. lactis secreting mouse IL-12 was essential for directing immune responses to LACK towards a protective T(H)1 response. CONCLUSIONS/SIGNIFICANCE: This report demonstrates the use of L. lactis as a live vaccine against L. major infection in BALB/c mice. The strains generated in this study provide the basis for the development of an inexpensive and safe vaccine against the human parasite Leishmania

Modern Approach to Education Based on Pedagogical Technologies

The article covers educational technology, educational technology, production technology, ancient education technology, course technology, ancient education, classical traditional education, modern traditional education, modern education, opinions on the content and essence of developmental education are stated. Definitions of course technology and modern education are given

Harnessing the thermoluminescence of Ge-doped silica flat-fibres for medical dosimetry

Study has been made of key thermoluminescence (TL) properties of Ge-doped silica flat-fibre, including TL glow curves, dose-rate dependency and reproducibility, the fibres being photon irradiated over the dose range 0.5- to 8 Gy, use being made of a medical linear accelerator (LINAC) operated at either 6- or 10 MV. Percentage depth doses (PDD) were also studied, comparison being made of fibre-measured PDD values against those obtained using an ionization chamber and standard TLD-100 and TLD-700 chips. The flat-fibre samples displayed a single prominent TL glow curve dosimetry peak at 249 °C, the structure of this remaining unchanged during repeat cycles of annealing and irradiation at different doses. For fixed dose, the TL responses of the samples also remained practically constant in use of five different dose-rates in the range100 MU/min to 500 MU/min. The effective atomic number (Zeff) of the flat-fibre was calculated to be 13.37, greater than soft tissue (7.42) but within the range of values for human bone (11.6–13.8). Using the 6 MV photon beam, PDD studies yielded a dmax of 1.5 cm, consistent with the value attained using the ionization chamber and the standard TLD chips. At 2 cm depth, the optical fibre samples showed good agreement to within −4%, 1.3% and 4% respectively with measurements made in use of the ionization chamber, standard TLD-100 chips and TLD-700 chips. The study represents part of an overall plan towards development of silica fiber-based dosimeters for radiotherapy and diagnostic radiology applications

Radioluminescence of Ge-doped silica optical fibre and Al2O3:C dosimeters

Using an electron accelerator producing a 6 MV X-ray photon beam several experimentally observed excitation phenomena that are associated with radioluminescence (RL) have been investigated, the signal originating from a Ge-doped silica optical fibre and commercial nanoDot Al2O3:C dosimeters. Using PMMA optical communication fibres the RL signals have been guided from the beam-delivery room out to the readout instrumentation that has been located beyond the concrete maze providing effective radiation shield. Ge-doped silica fibre memory effects and afterglow (phosphorescence) were compared with that of the commercial Al2O3:C dosimeter. Immediately following RL, observation was made of the decay curves of the afterglow signal of Al2O3:C. Conversely, there was little practically observable afterglow for the Ge-doped fibre used for the majority of present investigations (the dopant concentration of this being 3.6 wt %). Among three different concentration of Ge-doped fibres that were subsequently investigated in a follow-up study, the intensity of afterglow was found to be greatest for the more highly doped concentration (7.0 wt % Ge), with progressive reduction of the effect for the Ge 4.7 wt % and Ge 3.6 wt % fibres. These observations can be compared against the much more marked RL memory effect observed using the Al2O3:C chips. Current results pointto the Ge-doped silica optical fibre being a highly promising candidate for real-time RL dosimetry and sensing