Explore the vast range of titles available.

The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX). The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models. The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status. The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.

Nanoparticles consisting of single molecules of DNA condensed with polyethylene glycol-substituted lysine 30-mers efficiently transfect lung epithelium following intrapulmonary administration. Nanoparticles formulated with lysine polymers having different counterions at the time of DNA mixing have distinct geometric shapes: trifluoroacetate or acetate counterions produce ellipsoids or rods, respectively. Based on intracytoplasmic microinjection studies, nanoparticle ellipsoids having a minimum diameter less than the 25 nm nuclear membrane pore efficiently transfect non-dividing cells. This 25 nm size restriction corresponds to a 5.8 kbp plasmid when compacted into spheroids, whereas the 8–11 nm diameter of rod-like particles is smaller than the nuclear pore diameter. In mice, up to 50% of lung cells are transfected after dosing with a rod-like compacted 6.9 kbp lacZ expression plasmid, and correction of the CFTR chloride channel was observed in humans following intranasal administration of a rod-like compacted 8.3 kbp plasmid. To further investigate the potential size and shape limitations of DNA nanoparticles for in vivo lung delivery, reporter gene activity of ellipsoidal and rod-like compacted luciferase plasmids ranging in size between 5.3 and 20.2 kbp was investigated. Equivalent molar reporter gene activities were observed for each formulation, indicating that microinjection size limitations do not apply to the in vivo gene transfer setting.

DNA can be compacted using polyethylene glycol-substituted poly-l-lysine into discrete unimolecular (with respect to DNA) nanoparticles with minor diameter <20 nm that are stable in normal saline for at least 23 months at 4°C. We compared the activity of firefly luciferase in lungs of C57BL/6 mice that received 100 μg compacted plasmid in 25 μl saline (shown to be the optimal dose) via intratracheal or intranasal instillation with levels in animals given 100 μg naked plasmid or in untreated mice. Mice dosed with compacted DNA nanoparticles had peak activity of luciferase in lung at 2 days postinstillation, which declined in log-linear fashion with a half-life of 1.4 days. Luciferase activity in animals dosed with naked DNA was 200-fold less. Addition of polyethylene glycol to the complex was necessary for efficient gene transfer and animals that received DNA compacted with unmodified poly-l-lysine did not exhibit luciferase activity above background. Immunohistochemical staining for bacterial β-galactosidase 2 days after administration of a compacted lacZ expression plasmid (n = 8) revealed expression predominantly in the dependent portions of the right lungs of mice, in alveolar and airway epithelial cells, though macrophages and sometimes endothelial cells also were transfected. No staining for β-galactosidase was observed in uninjected animals (n = 4) or those dosed with naked lacZ plasmid (n = 7). Tissue survey for transgene expression shows expression only in lung and trachea following intranasal administration. Stable compacted DNA nanoparticles transfer exogenous genes to airway epithelium and show promise for lung gene therapy.

Instream large woody debris (LWD) provides several critical functions in riverine ecosystems, including sediment and nutrient retention, salmonid habitat enhancement, and stable colonization sites for incipient floodplain vegetation. In this study, the size and species composition of LWD in the Queets River, Washington, USA, were examined and compared with the size and species composition of forest trees from which they originated, in order to determine a depletion rate for LWD in the active channel. Increment cores from instream LWD were crossdated against cores from riparian conifers to estimate the year each LWD piece was recruited to the river channel. Debris pieces that were decayed or otherwise incompetent to provide cores were dated using standard14C techniques. Hardwood species (Alnus rubra, Populus trichocarpa, and Acer macrophyllum) were better represented among riparian forests than among instream LWD, and conifers (Picea sitchensis, Tsuga heterophylla, Pseudotsuga menziesii, and Thuja plicata) were better represented among LWD than in the adjacent riparian forest, suggesting that hardwoods were depleted from the channel faster than conifers. The depletion rate of coniferous LWD from the channel followed an exponential decay curve in which 80% of LWD pieces were <50 yr old, although some pieces have remained for up to 1400 yr. Although most wood is depleted from the channel within 50 yr, some wood is apparently buried in the floodplain and exhumed centuries later by lateral channel migration. The calculated depletion constant of 0.030 is equivalent to a half-life of ~20 yr, meaning that virtually all of the wood will have disappeared within 50 yr. This rapid depletion suggests that harvesting large conifers from the riparian zones of large streams could have adverse impacts within three to five decades.

Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor.

To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.

Graduate and post-graduate programs were initially developed by universities to increase discipline-specific mastery. Faculty members impact both the content and quality of such programs as they are responsible for making it relevant in the current climate while also addressing the changes envisaged for society tomorrow. Although studies exist regarding faculty competencies in various disciplines and for preparing future faculty members, there is a paucity of research specific to competencies necessary for faculty members who currently teach in doctoral leadership programs. This Delphi study explored 21st century competencies required in the next decade for faculty who currently teach in doctoral leadership programs in U.S. institutions.

Following a critical shortage of IVIG in the UK in 2006, the DoH commissioned a review of use. There was a perception that unlicensed indications for IVIG were proliferating without supportive clinical evidence, and that usage was increasing. The Demand Management Plan, Clinical Guidelines for IVIG use and the IVIG Database were the result.In year 1 the IVIG Database captured approximately 60% of IVIG use. Almost 500 000 g of IVIG (costing approximately £15 million) was infused for neurological indications. UK usage is static. Neurologists use 43% of total IVIG. 85% of the IVIG is used for CIDP, GBS, MMNCB and myasthenia gravis. Only 7% is used for indications with little evidence for use (“grey” indications in the Demand Management Plan). For indications where there is evidence for no benefit, only nine patients received 0.2% of the total IVIG use, 4/9 of these having received permission for exceptional use.The DoH has commended UK Neurologists on their appropriate, evidence-based prescribing. In year 2 of the database changes will be made to improve the quality of the data and achieve 100% data entry. Clinical trials in myasthenia gravis and other rarer conditions are needed to clarify the evidence for benefit. Evidence to support an update the Clinical Guidelines in 2010 is welcomed.

Nanoparticles containing DNA compacted with poly-l-lysine modified on an N-terminal cysteine with polyethylene glycol can effectively transfect cells of the airway epithelium when applied by the luminal route. To evaluate the toxicity of these nanoparticles, we administered 10 and 100 μg DNA compacted into nanoparticles suspended in normal saline by the intranasal route to mice and determined the pulmonary and systemic responses to this challenge, compared to administration of saline alone, and in some experiments, compared to administration of naked DNA, Escherichia coli genomic DNA, or lipofectin-complexed naked DNA. There was no systemic response to either dose of nanoparticles in serum chemistries, hematologic parameters, serum complement, IL-6, or MIP-2 levels or in the activity, growth, and grooming of the mice. Nanoparticles containing 10 μg DNA induced responses comparable to saline in all measures, including BAL cell counts and differentials and cytokine levels and histology. However, mice dosed with 100 μg DNA in nanoparticles had modest increases in BAL neutrophils 48 and 72 h after dosing, modest increases in BAL IL-6 and KC beginning 24 and 48 h, respectively, after dosing, and, on histology of the lung, a trace to 1+ mononuclear cell infiltrates about the pulmonary veins at 48 h, which were markedly reduced by 10 days and gone by 28 days after dosing. BAL neutrophil and cytokine responses were no greater than those entrained by naked DNA for up to 24 h. However, compared to administration of only 10 μg E. coli genomic DNA, the response to compacted DNA was much less. A low dose of lipofectin-complexed DNA (5 μg DNA) induced the same response as 20-fold higher doses of DNA nanoparticles. These data indicate that DNA nanoparticles have no measurable toxic effect at a dose of 10 μg and a very modest effect, which is not limiting, at a dose of 100 μg, which gives maximal gene expression. This favorable toxicity profile encourages development of stabilized compacted DNA for airway administration.

Attempts to classify certain habitats as vulnerable to invasion or plant traits as invasive have met with limited success and applicability. Clearly, not all plant invaders are able to exploit all habitats and not all habitats are equally susceptible to invasion. Here we argue that it is critical for a successful model for invasions to incorporate both environmental and species traits and present just such a framework. Although disturbance has been targeted as a crucial event which renders habitats vulnerable to invasion, disturbances are often integral parts of ecosystems (e.g. floods, tree-falls, fire, etc.) and are not always associated with invasion events. We argue that disturbances that are associated with invasions alter historical patterns of turnover, or flux, of resources in an ecosystem. Given this perspective on the relationship between invasions and disturbances, and the need to integrate species traits with those of invaded ecosystems, we have developed an approach to characterize plant invasion patterns that we call the 'Disturbed Resource-Flux Invasion Matrix' or DRIM. This is a 16-cell matrix that classifies habitats by the quality of changes in physical and chemical resource flux either increasing or decreasing flux relative to historical patterns. Within each matrix cell, it is then possible to apply basic ecological principles to target species traits that can facilitate successful invasion of habitats experiencing that particular kind of disturbance. We present examples from the literature of how habitats and species can be classified according to the DRIM, and demonstrate the application of this theoretical model.