Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells.

Cell adhesion to fibronectin is known to confer a temporally related cell adhesion-mediated drug resistance (CAM-DR). However, it is unknown whether cell adhesion during drug selection influences the more permanent form of acquired drug resistance. To examine this question, we compared the acquisition of mitoxantrone resistance in U937 cells adhered to fibronectin versus cells selected in a traditional suspension culture. Our data show that acquired drug resistance levels of resistance to mitoxantrone are 2- to 3-fold greater for cells adhered to fibronectin compared with cells in suspension culture. We also compared mechanism(s) of resistance associated with drug selection in suspension versus fibronectin-adherent cultures. Drug resistance in both suspension and fibronectin-adhered cultures correlated with reduced drug-induced DNA damage and diminished topoisomerase II levels and activity; however, mechanisms regulating topoisomerase II levels differed depending on culture conditions. In suspension cultures, a reduction in topoisomerase IIbeta levels was detected at both RNA and protein levels. Furthermore, the decreased expression of topoisomerase IIbeta mRNA levels correlated with decreased expression of NF-YA. In contrast, in spite of no changes in NF-YA or topoisomerase IIbeta RNA expression, topoisomerase IIbeta protein levels were decreased in fibronectin-adherent, drug-resistant cells. In addition, topoisomerase IIalpha protein levels (but not RNA levels) were reduced in drug resistance cells selected on fibronectin; however, no change in topoisomerase IIalpha was observed in cells selected with mitoxantrone in suspension culture. Taken together, our results suggest that the development of drug resistance models must consider interactions with the microenvironment to identify clinically relevant targets and mechanisms associated with acquired drug resistance.

Clinical Outcomes of Patients With Gastrointestinal Malignancies Participating in Phase I Clinical Trials.

OBJECTIVES: Early-phase clinical trials play a pivotal role in drug development. However, limited data are available on outcomes of gastrointestinal (GI) cancer patients enrolled in phase I clinical trials. Here, we evaluated the characteristics associated with survival in GI cancer patients participating in phase I clinical trials and attempted to validate previously established prognostic models. MATERIALS AND METHODS: All consecutive patients with advanced GI tumors who participated in phase I clinical trials at our institution from January 2007 to December 2013 and received at least 1 dose of the study drug were included. Cox regression models were used to estimate multivariable-adjusted hazard ratio (HR) and 95% confidence interval. RESULTS: In 243 study patients (median age, 62 y [range, 26 to 82 y]; 55% male), treatment included chemotherapy only (14%), targeted therapy (41%), chemotherapy+targeted therapy (42%), and others (2%) for the following disease types: pancreatic (42%), colorectal (34%), gastroesophageal (10%), hepatobiliary (13%), and others (2%). Response rate was 4%, with 38% achieving stable disease and 42% having progressive disease. Median survival was 5.8 months (range, 0.2 to 52.4 mo). Our multivariable Cox regression analyses included the following as predictors of survival: Eastern Cooperative Oncology Group performance score ≥1 (HR=1.76), prior systemic therapies ≥2 (HR=1.63), lactate dehydrogenase >618 IU/L (HR=1.85), sodium >135 mmol/L (HR=0.46), and white blood count >6×10/L (HR=1.5). Our data set was consistent with previous prognostic scores. CONCLUSIONS: This is the largest study to assess clinical outcomes in this patient population. Phase I trials provide clinical benefit to patients with advanced GI malignancies and should be recommended as a treatment option in appropriate patients.

Estimating plant-available nitrogen release from manures, composts, and specialty products.

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.

Suppression of Seedling Damping-Off Caused by Pythium ultimum, P. irregulare, and Rhizoctonia solani in Container Media Amended with a Diverse Range of Pacific Northwest Compost Sources.

ABSTRACT Suppression of seedling damping-off disease caused by Pythium spp. and Rhizoctonia solani is a potential benefit of formulating soilless container media with compost. Thirty-six compost samples from Pacific Northwest commercial composting facilities were analyzed for a number of physical, chemical, and biological properties, including suppression of damping-off caused by Pythium ultimum, P. irregulare, and R. solani. The samples were produced from diverse feedstocks and composting technol ogies; this was reflected in a large degree of variability in the measured properties. When mixed with sphagnum peat moss and inorganic aggregates, 67% of the compost samples significantly suppressed P. irregulare damping-off of cucumber, 64% suppressed P. ultimum damping-off of cucumber, and 17% suppressed damping-off of cabbage caused by R. solani. Suppression of Pythium damping-off was related to the potential of compost to support microbial activity and a qualitative index of ammonia volatilization. Suppression of Rhizoctonia damping-off was not related to any one compost factor. Currently available compost products potentially could provide commercially acceptable control of damping-off caused by Pythium spp., but it is necessary to fortify composts with microbial antagonists for the control of R. solani.

Decomposition and plant-available nitrogen in biosolids: laboratory studies, field studies, and computer simulation.

This research combines laboratory and field studies with computer simulation to characterize the amount of plant-available nitrogen (PAN) released when municipal biosolids are land-applied to agronomic crops. In the laboratory studies, biosolids were incubated in or on soil from the land application sites. Mean biosolids total C, organic N, and C to N ratio were 292 g kg(-1), 41.7 g kg(-1), and 7.5, respectively. Based on CO2 evolution at 25 degrees C and optimum soil moisture, 27 of the 37 biosolids-soil combinations had two decomposition phases. The mean rapid and slow fraction rate constants were 0.021 and 0.0015 d(-1), respectively, and the rapid fraction contained 23% of the total C assuming sequential decomposition. Where only one decomposition phase existed, the mean first order rate constant was 0.0046 d(-1). The mean rate constant for biosolids stored in lagoons for an extended time was 0.00097 d(-1). The only treatment process that was related to biosolids treatment was stabilization by storage in a lagoon. Biosolids addition rates (dry basis) ranged from 1.3 to 33.8 Mg ha(-1) with a mean value of 10.6 Mg ha(-1). A relationship between fertilizer N rate and crop response was used to estimate observed PAN at each site. Mean observed PAN during the growing season was 18.9 kg N Mg(-1) or 37% of the biosolids total N. Observed PAN was linearly related to biosolids total N. Predicted PAN using the computer model Decomposition, actual growing-season weather, actual analytical data, and laboratory decomposition kinetics compared well with observed PAN. The mean computer model prediction of growing-season PAN was 19.2 kg N Mg(-1) and the slope of the regression between predicted and observed PAN was not significantly different from unity. Predicted PAN obtained using mean decomposition kinetics was related to predicted PAN using actual decomposition kinetics suggesting that mean rate constants, actual weather, and actual analytical data could be used in estimation of PAN. There was a linear relationship between predicted N mineralization for the growing season and for the first year. For this study, the mean values for the growing season and year were 27 and 37% of the organic N, respectively.