Recent adoption of national rules for organic crop production have stimulated greater interest in meeting crop N needs using manures, composts, and other organic materials. This study was designed to provide data to support Extension recommendations for organic amendments. Specifically, our objectives were to (i) measure decomposition and N released from fresh and composted amendments and (ii) evaluate the performance of the model DECOMPOSITION, a relatively simple N mineralization/immobilization model, as a predictor of N availability. Amendment samples were aerobically incubated in moist soil in the laboratory at 22 degrees C for 70 d to determine decomposition and plant-available nitrogen (PAN) (n = 44), and they were applied preplant to a sweet corn crop to determine PAN via fertilizer N equivalency (n = 37). Well-composted materials (n = 14) had a single decomposition rate, averaging 0.003 d(-1). For uncomposted materials, decomposition was rapid (>0.01 d(-1)) for the first 10 to 30 d. The laboratory incubation and the full-season PAN determination in the field gave similar estimates of PAN across amendments. The linear regression equation for lab PAN vs. field PAN had a slope not different from one and a y-intercept not different than zero. Much of the PAN released from amendments was recovered in the first 30 d. Field and laboratory measurements of PAN were strongly related to PAN estimated by DECOMPOSITION (r(2) > 0.7). Modeled PAN values were typically higher than observed PAN, particularly for amendments exhibiting high initial NH(4)-N concentrations or rapid decomposition. Based on our findings, we recommend that guidance publications for manure and compost utilization include short-term (28-d) decomposition and PAN estimates that can be useful to both modelers and growers.

Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group. Conclusions Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day À1 on days 1 -3, followed by doxorubicin (20 mg m À2 ) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day À1 of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day À1 . Non-doselimiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for X8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day À1 . The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

Background The Notch signaling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. Patients and Methods Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN, and the downstream target HES1. Results 37 patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only 6 patients had stable disease as their best response. Median PFS was 1.8 months and median OS was 6.0 months. Conclusion In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.

3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

A systems trial was established in Oct. 2006 to evaluate management practices for organic production of northern highbush blueberry (Vaccinium corymbosum L.). The practices included: flat and raised planting beds; feather meal and fish emulsion fertilizer each applied at rates of 29 and 57 kg·ha−1 nitrogen (N); sawdust mulch, compost topped with sawdust mulch (compost + sawdust), or weed mat; and two cultivars, Duke and Liberty. Each treatment was irrigated by drip and weeds were controlled as needed. The planting was certified organic in 2008. After one growing season, allocation of biomass to the roots was greater when plants were grown on raised beds than on flat beds, mulched with organic mulch rather than a weed mat, and fertilized with the lower rate of N. Plants also allocated more biomass belowground when fertilized with feather meal than with fish emulsion. Although fish emulsion improved growth relative to feather meal in the establishment year, this was not the case the next year when feather meal was applied earlier. After two seasons, total plant dry weight (DW) was generally greater on raised beds than on flat beds, but the difference varied depending on fertilizer and the type of mulch used. Shoots and leaves accounted for 60% to 77% of total plant biomass, whereas roots accounted for 7% to 19% and fruit accounted for 4% to 18%. Plants produced 33% higher yield when grown on raised beds than on flat beds and had 36% higher yield with weed mat than with sawdust mulch. Yield was also higher when plants were fertilized with the low rate of fish emulsion than with any other fertilizer treatment in ‘Duke’ but was unaffected by fertilizer source or rate in ‘Liberty’. Although raised beds and sawdust or sawdust + compost produced the largest total plant DW, the greatest shoot growth and yield occurred when plants were mulched with weed mat or compost + sawdust on raised beds in both cultivars. The impact of these organic production practices on root development may affect the sustainability of these production systems over time, however, because plants with lower root-to-shoot ratios may be more sensitive to cultural or environmental stresses.

A long-term trial was established in Oct. 2006 in western Oregon to identify organic production systems for maximum yield and quality in highbush blueberry (Vaccinium corymbosum L.). The planting was transitional during the first year after planting and was certified organic during fruit production (2008–16). Treatments included planting method (on raised beds or flat ground), fertilizer source (granular feather meal or fish solubles), and rate (“low” and “high” rates of 29 and 57 kg·ha−1 N during establishment, increased incrementally as the planting matured to 73 and 140 kg·ha−1 N, respectively), mulch [sawdust, yard debris compost topped with sawdust (compost + sawdust), or black, woven polyethylene groundcover (weed mat)], and cultivar (‘Duke’ and ‘Liberty’). Mulches were replenished, as needed, and weeds were controlled throughout the study. Raised beds resulted in greater yield than flat ground during the establishment years but had less effect on yield once the plants were mature. After 9 years, cumulative yield was 22% greater on raised beds than on flat ground in ‘Liberty’ but was unaffected by planting method in ‘Duke’. Cumulative yield was also 10% greater with feather meal than with fish solubles, on average, and 4% greater with the low rate than with the high rate of fertilizer. ‘Duke’ was particularly sensitive to fertilizer source and produced 35% less yield overall with fish solubles than with feather meal. By contrast, there was relatively little effect of fertilizer source or rate on yield in ‘Liberty’. In five of 9 years, yield was 8% to 20% greater with weed mat than with sawdust or compost + sawdust. Mulch type had no effect on cumulative yield of ‘Duke’, but cumulative yield of ‘Liberty’ was 11% greater with weed mat than with sawdust or compost + sawdust. Soil temperature was warmer under weed mat than under sawdust, and plants on raised beds covered with weed mat required more irrigation than those grown on flat ground mulched with sawdust. ‘Duke’ produced heavier, larger, and firmer berries with lower total soluble solids (TSS) than ‘Liberty’. However, other treatment effects on berry quality were relatively small and inconsistent. For example, berry weight was greater on raised beds than on flat ground, on average, but only by 3% (0.06 g/berry). Plants on raised beds also produced berries with slightly lower TSS than those on flat ground (15.2% and 15.7%, respectively, in ‘Liberty’, and 13.1% and 13.3%, respectively in ‘Duke’). There was no effect of fertilizer source or rate on TSS in ‘Liberty’ (15.5% on average), whereas in ‘Duke’, TSS was highest when fertilized at the high (13.7%) or low (13.4%) rate of fish, and was lower when using feather meal (12.9% and 13.1% for low and high rate, respectively). Plants fertilized with fish produced firmer fruit than with feather meal in five of the 7 years in which the measurements were taken. Also, fertilization with the higher rate of either product increased berry firmness compared with the low rate in six of the 7 years. The impact of mulch was inconsistent through the study period. On average, ‘Duke’ berries were softest when fertilized with the low (173 g·mm−1 deflection) and high (176 g·mm−1) rates of feather meal and were the firmest with the high rate of fish (182 g·mm−1). In ‘Liberty’, the low rate of feather meal produced softer fruit (157 g·mm−1) than the other fertilizer treatments (162 g·mm−1 on average). When this study was initiated in 2006, the most common organic production system in this region was raised beds with sawdust mulch and fertilizing with a high rate of fish solubles. For this production system, yield for mature plants in our study (2014−16) was the equivalent of 8.9−12.3 t·ha−1 in ‘Duke’ and 11.8−23.7 t·ha−1 in ‘Liberty’. However, when plants were grown on raised beds with weed mat and fertilized with the high rate of feather meal, yield increased to 10.2−19.3 t·ha−1, depending on year, in ‘Duke’. By contrast, there was little effect of production system on yield of mature ‘Liberty’ plants. These yields, particularly for the best-performing treatment combination in ‘Duke’, are similar to what are observed in commercial conventional fields or organic farms using similar management practices. Our results showed that choice of organic production system can have significant impact on yield and economic costs and returns.

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