Stage is not a reliable indicator of tumor volume in non-small cell lung cancer: a preliminary analysis of the trans-tasman radiation oncology group 99-05 database

Background: Tumor volume has been shown to be a prognostic factor for the response of some tumors to radiotherapy. TNM stage has prognostic value for patients treated surgically for non-small cell lung cancer (NSCLC), but its value is less clear for patients treated by nonsurgical means. This may be because tumor size is not a consistent determinant of T stage or stage group. As part of the preliminary analyses for the Trans-Tasman Radiation Oncology Group 99-05 study, the authors performed this analysis to determine to what extent stage reflects tumor volume. Methods: In this prospective multicenter observational study, patients had to have histologically proven NSCLC, no evidence of disease beyond the primary site or thoracic lymph nodes, and been planned for radical radiotherapy with or without chemotherapy. Tumor volume measurements were based on computed tomography-based treatment planning images. Results: Four hundred four patients were available for analysis. There was a strong correlation between (log) maximum tumor diameter and (log) tumor volume (r = 0.93, p < 0.001). Although there was a highly significant trend of increasing volume with increasing T stage and stage group, when tumors were categorized into four groups according to increasing volume, there was only 55% concordance with T stage and 67% concordance with stage group. Conclusions: There is limited correlation between tumor size and disease stage in patients with NSCLC. This justifies documentation and investigation of size as a potential prognostic factor independent of stage. Maximum tumor diameter may be an adequate substitute for volume as a measurement of size.

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

High-Risk Merkel Cell Carcinoma of the Skin Treated With Synchronous Carboplatin/Etoposide and Radiation: A Trans-Tasman Radiation Oncology Group Study-TROG 96:07

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. Patients and Methods: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m(2) days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43-86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). Results: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. Conclusion: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation. (C) 2003 by American Society of Clinical Oncology.

The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX

The ataxia-telangiectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR) and activates downstream DNA-damage signaling pathways. Although the role of ATM in the cellular response to ionizing radiation has been well characterized, its role in response to other DNA-damaging agents is less well defined. We previously showed that genistein, a naturally occurring isoflavonoid, induced increased ATM protein kinase activity, ATM-dependent phosphorylation of p53 on serine 15 and activation of the DNA-binding properties of p53. Here. we show that genistein also induces phosphorylation of p53 at serines 6, 9, 20,46, and 392, and that genistein-induced accumulation and phosphorylation of p53 is reduced in two ATM-deficient human cell lines. Also, we show that genistein induces phosphorylation of ATM on serine 1981 and phosphorylation of histone H2AX on serine 139. The related bioflavonoids, daidzein and biochanin A, did not induce either phosphorylation of p53 or ATM at these sites. Like genistein, quercetin induced phosphorylation of ATM on serine 198 1, and ATM-dependent phosphorylation of histone H2AX on serine 139; however, p53 accumulation and phosphorylation on serines 6, 9, 15, 20, 46, and 392 occurred in ATM-deficient cells, indicating that ATM is not required for quercetin-induced phosphorylation of p53. Our data suggest that genistein and quercetin induce different DNA-damage induced signaling pathways that, in the case of genistein, are highly ATM-dependent but, in the case of quercetin, may be ATM-dependent only for some downstream targets. (C) 2003 Elsevier B.V. All rights reserved.

An evolutionary radiation of beeflies in semi-arid Australia: systematics of the Exoprosopini (Diptera : Bombyliidae)

Almost half of the 4822 described beeflies in the world belong to the subfamily Anthracinae, with most of the diversity found in three cosmopolitan tribes: Villini, Anthracini, and Exoprosopini. The Australian Exoprosopini previously contained three genera, Ligyra Newman, Pseudopenthes Roberts and Exoprosopa Macquart. Pseudopenthes is an Australian endemic, with two species including Ps. hesperis, sp. nov. from Western Australia. Two new species of the exoprosopine Atrichochira Hesse, Atr. commoni, sp. nov. and Atr. paramonovi, sp. nov., are also described from Australia, extending the generic distribution from Africa. Cladistic analysis clarified the phylogenetic relationships between the recognised groups of the Exoprosopini and determined generic limits on a world scale. Inclusion of 18 Australian exoprosopines placed the Australian species in the context of the world fauna. The Exoprosopini contains six large groups. The basal group I contains species previously included in Exoprosopa to which the name Defilippia Lioy is applied. Group II contains Heteralonia Rondani, Atrichochira, Micomitra Bowden, Pseudopenthes, and Diatropomma Bowden. Colossoptera Hull is newly synonymised with Heteralonia. Group III is a paraphyletic assemblage of Pterobates Bezzi and Exoprosopa including the Australian Ex. sylvana ( Fabricius). Ligyra is paraphyletic, forming two well-separated clades. The African clade is described as Euligyra Lambkin, gen. nov., which, together with Litorhina Bezzi and Hyperalonia Rondani, form group IV. The Australian group V is true Ligyra. The remaining monophyletic lineage of exoprosopines, group VI, the Balaana-group of genera, shows evidence of an evolutionary radiation of beeflies in semi-arid Australia. Phylogenetic analysis of all 42 species of the Balaana-group of genera formed a basis for delimiting genera. Seven new genera are described by Lambkin & Yeates: Balaana, Kapua, Larrpana, Munjua, Muwarna, Palirika and Wurda. Four non-Australian species belong to Balaana. Thirty two new Australian species are described: Bal. abscondita, Bal. bicuspis, Bal. centrosa, Bal. gigantea, Bal. kingcascadensis, K. corusca, K. irwini, K. westralica, Lar. collessi, Lar. zwicki, Mun. erugata, Mun. lepidokingi, Mun. paralutea, Mun. trigona, Muw. vitreilinearis, Pa. anaxios, Pa. basilikos, Pa. blackdownensis, Pa. bouchardi, Pa. cyanea, Pa. danielsi, Pa. decora, Pa. viridula, Pa. whyalla, W. emu, W. impatientis, W. montebelloensis, W. norrisi, W. patrellia, W. skevingtoni, W. windorah, and W. wyperfeldensis. The following new combinations are proposed: from Colossoptera: Heteralonia latipennis (Brunetti); from Exoprosopa: Bal. grandis (Pallas), Bal. efflatounbeyi (Paramonov), Bal. latelimbata ( Bigot), Bal. obliquebifasciata ( Macquart), Bal. tamerlan (Portschinsky), Bal. onusta ( Walker), Def. busiris (Jaennicke), Def. efflatouni ( Bezzi), Def. eritreae (Greathead), Def. gentilis ( Bezzi), Def. luteicosta ( Bezzi), Def. minos (Meigen), Def. nigrifimbriata ( Hesse), Def. rubescens ( Bezzi), K. adelaidica ( Macquart), Lar. dimidiatipennis ( Bowden), Muw. stellifera ( Walker), and Pa. marginicollis ( Gray); from Ligyra: Eu. enderleini ( Paramonov), Eu. mars ( Bezzi), Eu. monacha (Klug), Eu. paris ( Bezzi), Eu. sisyphus ( Fabricius), and Eu. venus (Karsch).

Crystallization and preliminary X-ray analysis of sulfite dehydrogenase from Stargeya novella

Crystals of purified heterodimeric sulfite dehydrogenase from Starkeya novella have been grown using vapour diffusion. X-ray diffraction data have been collected from crystals of the native protein at lambda=1.0 Angstrom and close to the iron absorption edge at lambda=1.737 Angstrom. The crystals belong to space group P2(1)2(1)2, with unit-cell parameters a=97.5, b=92.5, c=55.9 Angstrom. Native data have been recorded to 1.8 Angstrom resolution and Fe-edge data to 2.5 Angstrom.

Origin and diversity of the Sox transcription factor gene family: genome-wide analysis in Fugu rubripes

The SOX family of transcription factors are found throughout the animal kingdom and are important in a variety of developmental contexts. Genome analysis has identified 20 Sox genes in human and mouse, which can be subdivided into 8 groups, based on sequence comparison and intron-exon structure. Most of the SOX groups identified in mammals are represented by a single SOX sequence in invertebrate model organisms, suggesting a duplication and divergence mechanism has operated during vertebrate evolution. We have now analysed the Sox gene complement in the pufferfish, Fugu rubripes, in order to shed further light on the diversity and origins of the Sox gene family. Major differences were found between the Sox family in Fugu and those in humans and mice. In particular, Fugu does not have orthologues of Sry, Sox,15 and Sox30, which appear to be specific to mammals, while Sox19, found in Fugu and zebrafish but absent in mammals, seems to be specific to fishes. Six mammalian Sox genes are represented by two copies each in Fugu, indicating a large-scale gene duplication in the fish lineage. These findings point to recent Sox gene loss, duplication and divergence occurring during the evolution of tetrapod and teleost lineages, and provide further evidence for large-scale segmental or a whole-genome duplication occurring early in the radiation of teleosts. (C) 2004 Elsevier B.V. All rights reserved.

Crystallization and preliminary x-ray diffraction analysis of the unliganded human growth hormone receptor

The crystal structure of the extracellular domain of growth hormone receptor complexed to its ligand, growth hormone, has been known since 1992. However, no information exists for the unliganded form of the receptor. The human growth hormone receptor's extracellular ligand-binding domain, encompassing amino-acid residues 1 - 238, has been expressed in Escherichia coli, purified by anion ion-exchange chromatography and crystallized in its unliganded state by the hanging-drop vapour-diffusion method in 100 mM HEPES pH 7.0 containing 27.5%(w/v) PEG 5000 monomethyl ether and 200 mM ammonium sulfate as the co-precipitants. The crystals belong to the othorhombic space group C222(1), have unit-cell parameters a = 99.7, b = 112.2, c = 93.2 Angstrom and diffract to 2.5 Angstrom resolution using synchrotron radiation. The crystal structure will shed light on the nature of any conformation changes that occur upon ligand binding and will provide information to develop potential low-molecular-weight agonists/antagonists to treat clinical diseases in which the growth hormone receptor is implicated.

Phase-space analysis of bosonic spontaneous emission

We present phase-space techniques for the modelling of spontaneous emission in two-level bosonic atoms. The positive-P representation is shown to give a full and complete description within the limits of our model. The Wigner representation, even when truncated at second order, is shown to need a doubling of the phase-space to allow for a positive-definite diffusion matrix in the appropriate Fokker-Planck equation and still fails to agree with the full quantum results of the positive-P representation. We show that quantum statistics and correlations between the ground and excited states affect the dynamics of the emission process, so that it is in general non-exponential. (c) 2005 Elsevier B.V. All rights reserved.

Quantitative photoluminescence of broad band absorbing melanins: a procedure to correct for inner filter and re-absorption effects

We report methods for correcting the photoluminescence emission and excitation spectra of highly absorbing samples for re-absorption and inner filter effects. We derive the general form of the correction, and investigate various methods for determining the parameters. Additionally, the correction methods are tested with highly absorbing fluorescein and melanin (broadband absorption) solutions; the expected linear relationships between absorption and emission are recovered upon application of the correction, indicating that the methods are valid. These procedures allow accurate quantitative analysis of the emission of low quantum yield samples (such as melanin) at concentrations where absorption is significant. (c) 2004 Elsevier B.V. All rights reserved.

Effective cell-centred time-domain Maxwell's equations numerical solvers

This research work analyses techniques for implementing a cell-centred finite-volume time-domain (ccFV-TD) computational methodology for the purpose of studying microwave heating. Various state-of-the-art spatial and temporal discretisation methods employed to solve Maxwell's equations on multidimensional structured grid networks are investigated, and the dispersive and dissipative errors inherent in those techniques examined. Both staggered and unstaggered grid approaches are considered. Upwind schemes using a Riemann solver and intensity vector splitting are studied and evaluated. Staggered and unstaggered Leapfrog and Runge-Kutta time integration methods are analysed in terms of phase and amplitude error to identify which method is the most accurate and efficient for simulating microwave heating processes. The implementation and migration of typical electromagnetic boundary conditions. from staggered in space to cell-centred approaches also is deliberated. In particular, an existing perfectly matched layer absorbing boundary methodology is adapted to formulate a new cell-centred boundary implementation for the ccFV-TD solvers. Finally for microwave heating purposes, a comparison of analytical and numerical results for standard case studies in rectangular waveguides allows the accuracy of the developed methods to be assessed. © 2004 Elsevier Inc. All rights reserved.

Analysis of stirred mill performance using DEM simulation: Part 2 - Coherent flow structures, liner stress and wear, mixing and transport

Stirred Mills are becoming increasingly used for fine and ultra-fine grinding. This technology is still poorly understood when used in the mineral processing context. This makes process optimisation of such devices problematic. 3D DEM simulations of the flow of grinding media in pilot scale tower mills and pin mills are carried out in order to investigate the relative performance of these stirred mills. In the first part of this paper, media flow patterns and energy absorption rates and distributions were analysed to provide a good understanding of the media flow and the collisional environment in these mills. In this second part we analyse steady state coherent flow structures, liner stress and wear by impact and abrasion. We also examine mixing and transport efficiency. Together these provide a comprehensive understanding of all the key processes operating in these mills and a clear understanding of the relative performance issues. (C) 2006 Elsevier Ltd. All rights reserved.

Analysis of stirred mill performance using DEM simulation: Part 1 - Media motion, energy consumption and collisional environment

Stirred mills are becoming increasingly used for fine and ultra-fine grinding. This technology is still poorly understood when used in the mineral processing context. This makes process optimisation of such devices problematic. 3D DEM simulations of the flow of grinding media in pilot scale tower mills and pin mills are carried out in order to investigate the relative performance of these stirred mills. Media flow patterns and energy absorption rates and distributions are analysed here. In the second part of this paper, coherent flow structures, equipment wear and mixing and transport efficiency are analysed. (C) 2006 Published by Elsevier Ltd.

Anomalous scattering analysis of Agrobacterium radiobacter phosphotriesterase: the prominent role of iron in the heterobinuclear active site

Bacterial phosphotriesterases are binuclear metalloproteins for which the catalytic mechanism has been studied with a variety of techniques, principally using active sites reconstituted in vitro from apoenzymes. Here, atomic absorption spectroscopy and anomalous X-ray scattering have been used to determine the identity of the metals incorporated into the active site in vivo. We have recombinantly expressed the phosphotriesterase from Agrobacterium radiobacter (OpdA) in Escherichia coli grown in medium supplemented with 1 mM CoCl2 and in unsupplemented medium. Anomalous scattering data, collected from a single crystal at the Fe-K, Co-K and Zn-K edges, indicate that iron and cobalt are the primary constituents of the two metal-binding sites in the catalytic centre (alpha and P) in the protein expressed in E. coli grown in supplemented medium. Comparison with OpdA expressed in unsupplemented medium demonstrates that the cobalt present in the supplemented medium replaced zinc at the beta-position of the active site, which results in an increase in the catalytic efficiency of the enzyme. These results suggest an essential role for iron in the catalytic mechanism of bacterial phosphotriesterases, and that these phosphotriesterases are natively heterobinuclear iron-zinc enzymes.