Evaluation of Hydraulic Conductivity Estimates from Various Approaches with Groundwater Flow Models.

Significant efforts have been expended for improved characterization of hydraulic conductivity (K) and specific storage (Ss ) to better understand groundwater flow and contaminant transport processes. Conventional methods including grain size analyses (GSA), permeameter, slug, and pumping tests have been utilized extensively, while Direct Push-based Hydraulic Profiling Tool (HPT) surveys have been developed to obtain high-resolution K estimates. Moreover, inverse modeling approaches based on geology-based zonations, and highly parameterized Hydraulic Tomography (HT) have also been advanced to map spatial variations of K and Ss between and beyond boreholes. While different methods are available, it is unclear which one yields K estimates that are most useful for high resolution predictions of groundwater flow. Therefore, the main objective of this study is to evaluate various K estimates at a highly heterogeneous field site obtained with three categories of characterization techniques including: (1) conventional methods (GSA, permeameter, and slug tests); (2) HPT surveys; and (3) inverse modeling based on geology-based zonations and highly parameterized approaches. The performance of each approach is first qualitatively analyzed by comparing K estimates to site geology. Then, steady-state and transient groundwater flow models are employed to quantitatively assess various K estimates by simulating pumping tests not used for parameter estimation. Results reveal that inverse modeling approaches yield the best drawdown predictions under both steady and transient conditions. In contrast, conventional methods and HPT surveys yield biased predictions. Based on our research, it appears that inverse modeling and data fusion are necessary steps in predicting accurate groundwater flow behavior.

Stabilization of heavy metals in soil using two organo-bentonites.

Stabilization of Cu, Zn, Cd, Hg, Cr and As in soil using tetramethylammonium (TMA) and dodecyltrimethylammonium (DTMA) modified bentonites (T-Bents and D-Bents) as amendments was investigated. Toxicity characteristic leaching procedure (TCLP) was used to quantify the metal mobility after soil treatment. The structural parameters of modified bentonites, including the BET surface area, basal spacing and zeta potential were obtained as a function of the TMA and DTMA loading at 40, 80, 120, 160 and 200% of the bentonite's cation exchange capacity, respectively. The results indicated that the characteristics of the organo-bentonites fundamentally varied depending on the species and concentration of modifiers loaded on bentonite. T-Bents and D-Bents manifested distinct immobilization effectiveness towards various metals. In association with the organo-bentonite characteristics, the main interactive mechanisms for Cu, Zn and Cd proceeded via cation exchange, Hg proceeded via physical adsorption and partitioning, Cr and As proceeded via specific adsorption and electrostatic attraction, respectively. This study provided operational and mechanistic basis for optimizing the organic clay synthesis and selecting as the appropriate amendment for remediation of heavy metal contaminated soils.

Cosolvent Effects on Dechlorination of Soil-Sorbed Polychlorinated Biphenyls Using Bentonite Clay-Templated Nanoscale Zero Valent Iron.

Zero-valent iron synthesized using bentonite clay as a template (CZVI) was tested for its reactivity toward polychlorinated biphenyl (PCB) dechlorination in soil slurries. Aqueous-phase decachlorobiphenyl (PCB209) was rapidly dechlorinated by CZVI with a reaction rate 10 times greater than that by conventional nanoscale zerovalent iron. This superior reactivity was due largely to the nanoscale size (∼0.5 nm) of the ZVI particles located in the clay galleries. In soil slurries where PCB209 was strongly soil-bound, adding ethanol as an organic cosolvent led to increased PCB209 desorption into the liquid phase, thereby enhancing the PCB209 dechlorination with CZVI. The more effective PCB209 dechlorination in such a cosolvent system also promoted the subsequent stepwise dechlorinative process, leading to a relatively more removal of chlorine in the product mixture. The dechlorination became more rapid as the ethanol fraction increased from 10% to 50%, due apparently to the increasingly greater PCB209 desorption and thus facilitated contact with CZVI. Further increase in ethanol fraction above 50% led to an insignificant enhancement in degradation rate, due partially to attenuated contact of PCB209 with CZVI and reduced proton source from limited water content in the liquid. It is suggested that addition of organic cosolvents may make CZVI potentially useful for remediation of soils containing halogenated organic contaminants.

Pharmacokinetics of creatine.

Research has demonstrated that creatine supplementation has some therapeutic benefit with respect to muscle function and more recently neurological function. Despite the growing body of literature on the pharmacologic effect of creatine, very little is known about the disposition of creatine after supraphysiologic doses. The movement of creatine throughout the body is governed by transport processes which impact the absorption of creatine from the intestine, clearance of creatine from the kidney, and access of creatine to target tissues. With repeated doses of creatine, it appears that the clearance of creatine decreases mainly due to the saturation of skeletal muscle stores. Insulin and insulin-stimulating foods appear to enhance muscle uptake of creatine but at the same time, high carbohydrate meals may slow the absorption of creatine from the intestine. Little is known about creatine disposition in special populations including the elderly and patients with neuromuscular disease. Knowledge of creatine disposition in these clinically relevant populations can help remove some of the guess work of dose selection during clinical trials.

Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.

Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer.

Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.

Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth.

PURPOSE: The androgen receptor (AR) is a ligand-dependent transcription factor that mediates gene expression and growth of normal and malignant prostate cells. In prostate tumors that recur after androgen withdrawal, the AR is highly expressed and transcriptionally active in the absence of testicular androgens. In these "androgen-independent" tumors, alternative means of AR activation have been invoked, including regulation by growth factors and their receptors in prostate cancer recurrence. EXPERIMENTAL DESIGN AND RESULTS: In this report, we show that HER receptor tyrosine kinases 1 through 4 are expressed in the CWR-R1 recurrent prostate cancer cell line; their stimulation by epidermal growth factor (EGF) and heregulin activates downstream signaling, including mitogen-activated protein kinase and phosphatidylinositol-3 kinase and Akt pathways. We show that heregulin activates HER2 and HER3 and increases androgen-dependent AR transactivation of reporter genes in CWR-R1 cells. Tyrosine phosphorylation of HER2 and HER3, AR transactivation, and cell proliferation induced by heregulin were more potently inhibited by the EGFR/HER2 dual tyrosine kinase inhibitor GW572016 (lapatinib) than the EGFR-specific inhibitor ZD1839 (gefitinib). Basal proliferation in the absence of growth factors was also inhibited by GW572016 to a greater extent than ZD1839, suggesting that low level HER2/HER3 activation perhaps by an autocrine pathway contributes to the proliferation signal. CONCLUSIONS: These data indicate that heregulin signaling through HER2 and HER3 increases AR transactivation and alters growth in a recurrent prostate cancer cell line. Therefore, inhibition of low-level HER2 signaling may be a potential novel therapeutic strategy in prostate cancer.