Adenovirus-mediated interleukin-12 gene transfer combined with <it>cytosine deaminase </it>followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice

<p>Abstract</p> <p>Background</p> <p>Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors.</p> <p>Methods</p> <p>Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-γ production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-γ production.</p> <p>Results</p> <p>The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-γ production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time.</p> <p>Conclusion</p> <p>The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers.</p

Understanding phosphorus mobility and bioavailability in the hyporheic zone of a chalk stream

This paper investigates the changes in bioavailable phosphorus (P) within the hyporheic zone of a groundwater-dominated chalk stream. In this study, tangential flow fractionation is used to investigate P associations with different size fractions in the hyporheic zone, groundwater and surface water. P speciation is similar for the river and the chalk aquifer beneath the hyporheic zone, with ‘dissolved’ P (<10 kDa) accounting for ~90% of the P in the river and >90% in the deep groundwaters. Within the hyporheic zone, the proportion of ‘colloidal’ (10 kDa) and ‘particulate’ (>0.45 μm) P is higher than in either the groundwater or the surface water, accounting for ~30% of total P. Our results suggest that zones of interaction within the sand and gravel deposits directly beneath and adjacent to river systems generate colloidal and particulate forms of fulvic-like organic material and regulate bioavailable forms of P, perhaps through coprecipitation with CaCO3. While chalk aquifers provide some degree of protection to surface water ecosystems through physiochemical processes of P removal, where flow is maintained by groundwater, ecologically significant P concentrations (20–30 μg/L) are still present in the groundwater and are an important source of bioavailable P during baseflow conditions. The nutrient storage capacity of the hyporheic zone and the water residence times of this dynamic system are largel

Spectroscopy of 25,65/67Mn: Strong coupling in the N = 40 "island of inversion"

Excited states in 63,65,67Mn were studied via in-beam γ -ray spectroscopy following knockout reactions from 68Fe. Similar level schemes, consisting of the 11/2−, 9/2−, 7/2− and 5/2− g.s. level sequence, connected by I → I − 1 transitions, were established, the first time for 65,67Mn. Their level structures show features consistent with strongly-coupled rotational bands with K = 5/2. State-of-the-art shellmodel calculations with the modified LNPS effective interaction reproduce the observed levels remarkably well and suggest the dominance of 4-particle-4-hole neutron configurations for all the states. The data on the low-lying excited states of odd-mass 53−67Mn provide a textbook example of nuclear structure evolution from weak coupling through decoupling to strong coupling along a single isotopic chain on the n-rich side of the β stability line. These results help to deepen our understanding of the N = 40 “island of inversion”