Non-Ideal Behavior in Solvent Extraction

This report presents a summary of the work performed to meet FCR&D level 3 milestone M31SW050801, 'Complete the year-end report summarizing FY11 experimental and modeling activities.' This work was carried out under the auspices of the Non-Ideality in Solvent Extraction Systems FCR&D work package. The report summarizes our initial considerations of potential influences that non-ideal chemistry may impose on computational prediction of outcomes in solvent extraction systems. The report is packaged into three separate test cases where a robustness of the prediction by SXFIT program is under scrutiny. The computational exercises presented here emphasize the importance of accurate representation of both an aqueous and organic mixtures when modeling liquid-liquid distribution systems. Case No.1 demonstrates that non-ideal behavior of HDEHP in aliphatic diluents, such as n-dodecane, interferes with the computation. Cases No.2 and No.3 focus on the chemical complexity of aqueous electrolyte mixtures. Both exercises stress the need for an improved thermodynamic model of an aqueous environment present in the europium distribution experiments. Our efforts for year 2 of this project will focus on the improvements of aqueous and non-aqueous solution models using fundamental physical properties of mixtures acquired experimentally in our laboratories

Thermodynamics and Kinetics of Advanced Separations Systems ? FY 2010 Summary Report

This report presents a summary of the work performed in the area of thermodynamics and kinetics of advanced separations systems under the Fuel Cycle Research and Development (FCR&D) program during FY 2010. Thermodynamic investigations into metal extraction dependencies on lactate and HDEHP have been performed. These metal distribution studies indicate a substantial deviation from the expected behavior at conditions that are typical of TALSPEAK process operational platform. These studies also identify that no thermodynamically stable mixed complexes exist in the aqueous solutions and increasing the complexity of the organic medium appears to influence the observed deviations. Following on from this, the first calorimetric measurement of the heat of extraction of americium across a liquid-liquid boundary was performed

CA19-9 as a predictor of tumor response and survival in patients with advanced pancreatic cancer treated with gemcitabine based chemotherapy

The aim of this study was to determine the predictive role of pretreatment carbohydrate antigen 19-9 (CA19-9) measurement and its change after one cycle of gemcitabine-based therapy for response, time to progression (TTP) and overall survival (OS).Analyses were derived from three consecutive gemcitabine-containing phase II clinical trials between 1997 and 2004.A total of 111 patients with pancreas cancer was studied. Baseline CA19-9 concentrations were dichotomized near the median. Lower baseline CA19-9 levels were positively associated with OS (median 9.1 vs 6.1 months, P  = 0.0057) and TTP (median 6.4 vs 4.2 months, P  = 0.0044).The covariate adjusted hazard ratio (HR) for progression among patients with baseline CA19-9 ≥ 1000 ng/mL was HR = 1.94 (95% CI 1.24–3.02), with P  = 0.0035. The covariate adjusted risk of death among patients with baseline CA19-9 ≥ 1000 ng/ml was similarly elevated: HR = 1.90 (95% CI 1.23–2.94), with P  = 0.0039. Change in CA19-9 levels from baseline to the end of treatment cycle 1 did not predict objective response ( P  = 0.75). There was somewhat longer OS (median 8.7 vs 7.1 months) and TTP (median 7.1 vs 5.4 months) in patients with ≥50% reduction in serum CA19-9 concentrations, but this was not statistically significant ( P  = 0.74 and 0.81, respectively).Baseline CA19-9 levels may predict survival in patients with advanced pancreas cancer. The change in CA19-9 levels determined within 1 month of the initiation of therapy did not predict treatment outcome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79310/1/j.1743-7563.2010.01290.x.pd

Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102207/1/lt23757.pd

Toward understanding the thermodynamics of TALSPEAK process. Medium effects on actinide complexation

The ingenious combination of lactate and diethylenetriamine-N,N,N’,N”,N”-pentaacetic acid (DTPA) as an aqueous actinide-complexing medium forms the basis of the successful separation of americium and curium from lanthanides known as the TALSPEAK process. While numerous reports in the prior literature have focused on the optimization of this solvent extraction system, considerably less attention has been devoted to the understanding of the basic thermodynamic features of the complex fluids responsible for the separation. The available thermochemical information of both lactate and DTPA protonation and metal complexation reactions are representative of the behavior of these ions under idealized conditions. Our previous studies of medium effects on lactate protonation suggest that significant departures from the speciation predicted based on reported thermodynamic values should be expected in the TALSPEAK aqueous environment. Thermodynamic parameters describing the separation chemistry of this process thus require further examination at conditions significantly removed from conventional ideal systems commonly employed in fundamental solution chemistry. Such thermodynamic characterization is the key to predictive modelling of TALSPEAK. Improved understanding will, in principle, allow process technologists to more efficiently respond to off-normal conditions during large scale process operation. In this report, the results of calorimetric and potentiometric investigations of the effects of aqueous electrolytes on the thermodynamic parameters for lactate protonation and lactate complexation of americium and neodymium will be presented. Studies on the lactate protonation equilibrium will clearly illustrate distinct thermodynamic variations between strong electrolyte aqueous systems and buffered lactate environment

Understanding the solution behavior of minor actinides in the presence of EDTA(4-), carbonate, and hydroxide ligands

Understanding the solution behavior of minor actinides in the presence of EDTA(4-), carbonate, and hydroxide ligand

Screening for Depression, Sleep-Related Disturbances, and Anxiety in Patients with Adenocarcinoma of the Pancreas: A Preliminary Study

Purpose. Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas. Materials and Methods. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms. Results. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup. Conclusions. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course

Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma

BACKGROUND. Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m 2 /cycle) and either high-dose ifosfamide (12 g/m 2 /cycle) or standard-dose ifosfamide (6 g/m 2 /cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported. METHODS. Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity. RESULTS. Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0–24 values ( r = 0.97, 0.94, and 0.95; P < .0001). Patients who experienced a grade 3–4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0–2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity. CONCLUSIONS. The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1-hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56045/1/22669_ftp.pd

Randomized clinical trial of a brief and extensive dyadic intervention for advanced cancer patients and their family caregivers

Background Few intervention programs assist patients and their family caregivers to manage advanced cancer and maintain their quality of life (QOL). This study examined (i) whether patient–caregiver dyads (i.e., pairs) randomly assigned to a brief or extensive dyadic intervention (the FOCUS Program) had better outcomes than dyads randomly assigned to usual care and (ii) whether patients' risk for distress and other factors moderated the effect of the brief or extensive program on outcomes. Methods Advanced cancer patients and their caregivers ( N  = 484 dyads) were stratified by patients' baseline risk for distress (high versus low), cancer type (lung, colorectal, breast, or prostate), and research site and then randomly assigned to a brief (three‐session) or extensive (six‐session) intervention or control. The interventions offered dyads information and support. Intermediary outcomes were appraisals (i.e., appraisal of illness/caregiving, uncertainty, and hopelessness) and resources (i.e., coping, interpersonal relationships, and self‐efficacy). The primary outcome was QOL. Data were collected prior to intervention and post‐intervention (3 and 6 months from baseline). The final sample was 302 dyads. Repeated measures MANCOVA was used to evaluate outcomes. Results Significant group by time interactions showed that there was an improvement in dyads' coping ( p  < 0.05), self‐efficacy ( p  < 0.05), and social QOL ( p  < 0.01) and in caregivers' emotional QOL ( p  < 0.05). Effects varied by intervention dose. Most effects were found at 3 months only. Risk for distress accounted for very few moderation effects. Conclusions Both brief and extensive programs had positive outcomes for patient–caregiver dyads, but few sustained effects. Patient–caregiver dyads benefit when viewed as the ‘unit of care’. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96760/1/pon3036.pd

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae, and has been implicated in oncogenic cell transformation, tumorigenesis, and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy, and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models, and patient samples, and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation, and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models, and human pancreatic tumors, and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation, and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo, Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK, and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo), is responsible for promoting resistance to therapies, and may serve as a prognostic/predictive biomarker and target in PC