US Highway 65 / IA-330 Improvements Polk and Jasper Counties, Iowa : Limited Phase I, Environmental Site Assessment, 1998

The Iowa Department of Transportation (IDOT) is currently considering improvements for US Highway 65 (US-65) and Iowa State Highway 330 (IA-330) in Polk and Jasper Counties, Iowa. As part of its project planning effort, IDOT is preparing an Environmental Assessment (EA) report which will include a section entitled "Hazardous Waste" to identify known sites in or near the proposed corridors that are, or could be, contaminated with hazardous or petroleum substances.

3531: Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients (pts) with locally advanced, k-ras-mutated rectal cancer (LARC): A phase I/II trial SAKK 41/08

Background: K-ras mutation is found in up to 40% of LARC. Sor is a multitarget tyrosine kinase inhibitor including raf and VEGFR and has demonstrated radiosensitizing effects. Sor might improve outcome of standard preoperative radio-chemotherapy in patients with k-ras mutated LARC. Methods: Pts with k-ras mutated T3-4 and/or N+, M0 disease by MRI were included. Recommended doses from phase I part consisted of RT 1.8 Gy/day x25 with Cape 825mg/m2bid x 33 in combination with Sor 400mg/d. The primary endpoint for the phase II part was pathological complete response (pCR) prospectively defined as grade 3 (near complete regression) or 4 (complete regression) in the histological grading system according to Dworak (DC). A pCR rate of 8% or lower was considered uninteresting and of 22% or higher was promising. Secondary endpoints included sphincter preservation, R0 resection, downstaging and safety. Results: 54 pts were treated in 18 centers in Switzerland und Hungary, 40 pts were included into the single arm phase II part. Median dose intensity per day was 100.0% for RT, 98.6% for Cape and 100.0% for Sor respectively. pCR rate was 60.0% (95%CI: 43.3%, 75.1%) by central independent pathological review (15.0% DC grade 4; 45.0% DC grade 3). Sphincter preservation was achieved in 89.5%, R0 resection in 94.7% and downstaging in 81.6% of the pts. The most common grade 3 toxicities included diarrhea (15.0%), skin toxicity outside of the RT field (12.5%), pain (7.5%), skin toxicity in RT field, proctitis, fatigue and cardiac ischemia (each 5.0%). Laboratory AEs grade 3/4 were neutropenia (1 pt grade 4; 1 grade 3), creatinine elevation (1 pt grade 3). Conclusions: The combination of Sor to standard RCT with Cape in k-ras mutated LARC tumors is highly active with acceptable toxicity and deserves further investigation.

Optimal designs for evaluating a series of treatments

Several articles in this journal have studied optimal designs for testing a series of treatments to identify promising ones for further study. These designs formulate testing as an ongoing process until a promising treatment is identified. This formulation is considered to be more realistic but substantially increases the computational complexity. In this article, we show that these new designs, which control the error rates for a series of treatments, can be reformulated as conventional designs that control the error rates for each individual treatment. This reformulation leads to a more meaningful interpretation of the error rates and hence easier specification of the error rates in practice. The reformulation also allows us to use conventional designs from published tables or standard computer programs to design trials for a series of treatments. We illustrate these using a study in soft tissue sarcoma.

Chemical studies of elements with Z ⩾ 104 in gas phase

Chemical investigations of superheavy elements in the gas-phase, i.e. elements with Z≥104Z≥104, allow assessing the influence of relativistic effects on their chemical properties. Furthermore, for some superheavy elements and their compounds quite unique gas-phase chemical properties were predicted. The experimental verification of these properties yields supporting evidence for a firm assignment of the atomic number. Prominent examples are the high volatility observed for HsO4 or the very weak interaction of Cn with gold surfaces. The unique properties of HsO4 were exploited to discover the doubly-magic even–even nucleus 270Hs and the new isotope 271Hs. The combination of kinematic pre-separation and gas-phase chemistry allowed gaining access to a new class of relatively fragile compounds, the carbonyl complexes of elements Sg through Mt. A not yet resolved issue concerns the interaction of Fl with gold surfaces. While competing experiments agree on the fact that Fl is a volatile element, there are discrepancies concerning its adsorption on gold surfaces with respect to its daughter Cn. The elucidation of these and other questions amounts to the fascination that gas-phase chemical investigations exert on current research at the extreme limits of chemistry today.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

DAQ00152 Herbicide Tolerance Screening in Northern Region (Phase IV)

The previous projects (phase I - III) highlighted that northern region wheat and barley cultivars differ considerably in their sensitivity to herbicides. The new project will focus on increased screening of advanced breeding lines and new cultivars lines to commonly used herbicides, for barley, chickpea and wheat. Studies on impact of environment on herbicide x genotype responses will also be undertaken with the national team. The new information will be added to the existing information package on herbicide tolerance. Thus, adverse impacts of herbicides on productivity in northern region will be reduced, as growers and agronomists will select safer herbicides for their sown variety, or select more tolerant varieties for their important herbicides.

Phase diagram and dielectric studies of binary organic materials

The phase equilibrium studies of organic system, involving resorcinol (R) and p-dimethylaminobenzaldehyde (DMAB), reveal the formation of a 1:1 molecular complex with two eutectics. The heat of mixing, entropy of fusion, roughness parameter, interfacial energy, and the excess thermodynamic functions were calculated based on enthalpy of fusion data determined via differential scanning calorimetric (DSC) method. X-ray powder diffraction studies confirm that the eutectics are not simple mechanical mixture of the components under investigation. The spectroscopic investigations (IR and NMR) suggest the occurrence of hydrogen bonding between the components forming the molecular complex. The dielectric measurements, carried out on hot-pressed addition compound (molecular complex), show higher dielectric constant at 320 K than that of individual components. The microstructural investigations of eutectic and addition compound indicate dendritic and faceted morphological features. (C) 2000 Elsevier Science B.V. All rights reserved.

Three-dimensional models of mantle convection : influence of phase transitions and temperature-dependent viscosity

Two of the most important questions in mantle dynamics are investigated in three separate studies: the influence of phase transitions (studies 1 and 2), and the influence of temperature-dependent viscosity (study 3).

(1) Numerical modeling of mantle convection in a three-dimensional spherical shell incorporating the two major mantle phase transitions reveals an inherently three-dimensional flow pattern characterized by accumulation of cold downwellings above the 670 km discontinuity, and cylindrical 'avalanches' of upper mantle material into the lower mantle. The exothermic phase transition at 400 km depth reduces the degree of layering. A region of strongly-depressed temperature occurs at the base of the mantle. The temperature field is strongly modulated by this partial layering, both locally and in globally-averaged diagnostics. Flow penetration is strongly wavelength-dependent, with easy penetration at long wavelengths but strong inhibition at short wavelengths. The amplitude of the geoid is not significantly affected.

(2) Using a simple criterion for the deflection of an upwelling or downwelling by an endothermic phase transition, the scaling of the critical phase buoyancy parameter with the important lengthscales is obtained. The derived trends match those observed in numerical simulations, i.e., deflection is enhanced by (a) shorter wavelengths, (b) narrower up/downwellings (c) internal heating and (d) narrower phase loops.

(3) A systematic investigation into the effects of temperature-dependent viscosity on mantle convection has been performed in three-dimensional Cartesian geometry, with a factor of 1000-2500 viscosity variation, and Rayleigh numbers of 10^5-10^7. Enormous differences in model behavior are found, depending on the details of rheology, heating mode, compressibility and boundary conditions. Stress-free boundaries, compressibility, and temperature-dependent viscosity all favor long-wavelength flows, even in internally heated cases. However, small cells are obtained with some parameter combinations. Downwelling plumes and upwelling sheets are possible when viscosity is dependent solely on temperature. Viscous dissipation becomes important with temperature-dependent viscosity.

The sensitivity of mantle flow and structure to these various complexities illustrates the importance of performing mantle convection calculations with rheological and thermodynamic properties matching as closely as possible those of the Earth.

A joined analysis of two European Organization for the Research and Treatment of Cancer (EORTC) studies to evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of elderly patients with metastatic breast cancer.

We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3-4 toxicity or antitumor activity and patients' baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m(2) every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.

Potent functional antibody responses elicited by HIV-I DNA priming and boosting with heterologous HIV-1 recombinant MVA in healthy Tanzanian adults.

UNLABELLED: Vaccine-induced HIV antibodies were evaluated in serum samples collected from healthy Tanzanian volunteers participating in a phase I/II placebo-controlled double blind trial using multi-clade, multigene HIV-DNA priming and recombinant modified vaccinia Ankara (HIV-MVA) virus boosting (HIVIS03). The HIV-DNA vaccine contained plasmids expressing HIV-1 gp160 subtypes A, B, C, Rev B, Gag A, B and RTmut B, and the recombinant HIV-MVA boost expressed CRF01_AE HIV-1 Env subtype E and Gag-Pol subtype A. While no neutralizing antibodies were detected using pseudoviruses in the TZM-bl cell assay, this prime-boost vaccination induced neutralizing antibodies in 83% of HIVIS03 vaccinees when a peripheral blood mononuclear cell (PBMC) assay using luciferase reporter-infectious molecular clones (LucR-IMC) was employed. The serum neutralizing activity was significantly (but not completely) reduced upon depletion of natural killer (NK) cells from PBMC (p=0.006), indicating a role for antibody-mediated Fcγ-receptor function. High levels of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies against CRF01_AE and/or subtype B were subsequently demonstrated in 97% of the sera of vaccinees. The magnitude of ADCC-mediating antibodies against CM235 CRF01_AE IMC-infected cells correlated with neutralizing antibodies against CM235 in the IMC/PBMC assay. In conclusion, HIV-DNA priming, followed by two HIV-MVA boosts elicited potent ADCC responses in a high proportion of Tanzanian vaccinees. Our findings highlight the potential of HIV-DNA prime HIV-MVA boost vaccines for induction of functional antibody responses and suggest this vaccine regimen and ADCC studies as potentially important new avenues in HIV vaccine development. TRIAL REGISTRATION: Controlled-Trials ISRCTN90053831 The Pan African Clinical Trials Registry ATMR2009040001075080 (currently PACTR2009040001075080).

A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir.

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.

Determination of the molecular weight distribution of non-enzymatic browning products formed by roasting of glucose and glycine and studies on their effects on NADPH-cytochrome c-reductase and glutathione-S-transferase in Caco-2 cells

After thermal treatment of a mixture of glucose and glycine for 2 h at 125 degreesC, about 60% of the starting material was converted into nonsoluble, black pigments, whereas 40% of the mixture was still water-soluble. Dialysis of the latter fraction revealed 30.4% of low molecular weight compounds (LMWs; MW <10 000 De) and 10.0% high-molecular weight products [HMWs; MW greater than or equal to 10000 Dal. The water-soluble Maillard reaction products (MRPs) were separated by gel permeation chromatography and ultrafiltration, revealing that 60% of the water-soluble products of the total carbohydrate/amino acid mixture had MWs <1 000 Da and consisted mainly of non-coloured reaction products. MRPs with MWs between 1000 and 30000 Da were Found in comparatively low yields (about 1.3%). In contrast, about 31.1% of the MRPs exhibited MWs > 30000 Da, amongst which 14.5% showed MWs > 100000 Da, thus indicating an oligomerisation of LMWs to melanoidins under roasting conditions. To investigate the physiological effects of these MRPs, xenobiotic enzyme activities were analysed in intestinal Caco-2 cells. For Phase-I NADPH-cytochrome c-reductase, the activity in the presence of the LMW and HMW fraction was decreased by 13% and 22%: respectively. Phase-II glutathione-S-transferase activity decreased by 15% and 18%, respectively, after incubation with the LMW and the HMW fractions. Considering the different yields, 30% and 10%, respectively, of the LMW and the HMW fractions, the total amount of the LMW fraction present in the glucose-glycine mixture is more active in modulating three enzyme activities than that of the HMW fraction.

Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

I must walk through the gate : an ontological necessity

This research is a self-study into my life as an athlete, elementary school teacher, leamer, and as a teacher educator/academic. Throughout the inquiry, I explore how my beliefs and values infused my lived experiences and ultimately influenced my constructivist, humanist, and ultimately my holistic teaching and learning practice which at times disrupted the status quo. I have written a collection of narratives (data generation) which embodied my identity as an unintelligent student/leamer, a teacher/learner, an experiential learner, a tenacious participant, and a change agent to name a few. As I unpack my stories and hermeneutically reconstruct their intent, I question their meaning as I explore how I can improve my teaching and learning practice and potentially effect positive change when instructing beginning teacher candidates at a Faculty of Education. At the outset I situate my story and provide the necessary political, social, and cultural background information to ground my research. I follow this with an in depth look at the elements that interconnect the theoretical framework of this self-study by presenting the notion of writing at the boundaries through auto ethnography (Ellis, 2000; Ellis & Bochner, 2004) and writing as a method of inquiry (Richardson, 2000). The emergent themes of experiential learning, identity, and embodied knowing surfaced during the data generation phase. I use the Probyn' s (1990) .. metaphor of locatedness to unpack these themes and ponder the question, Where is experience located? I deepen the exploration by layering Drake's (2007) KnowlDo/Be framework alongside locatedness and offer descriptions of learning moments grounded in pedagogical theories. In the final phase, I introduce thirdspace theory (Bhabha, 1994; Soja, 1996) as a space that allowed me to puzzle educational dilemmas and begin to reconcile the binaries that existed in my life both personally, and professionally. I end where I began by revisiting the questions that drove this study. In addition, Ireflect upon the writing process and the challenges that I encountered while immersed in this approach and contemplate the relevance of conducting a self-study. I leave the reader with what is waiting for me on the other side of the gate, for as Henry James suggested, "Experience is never limited, and it is never complete."

Choice of designs and doses for early phase trials

This paper reviews state-of-art statistical designs for dose-escalation procedures in first-into-man studies. The main focus will be on studies in oncology, as most statistical procedures for phase I trials have been proposed in this context. Extensions to situations such as the observation of bivariate outcomes and healthy volunteer studies are also discussed. The number of dose levels and cohort sizes used in early phase trials are considered. Finally, this paper raises some practical issues for dose-escalation procedures.