Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer

Purpose: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. © 2005 by American Society of Clinical Oncology.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Functional significance of male attractants of Bactrocera tryoni (Diptera: Tephritidae) and underlying mechanisms

This project elucidated functional role of phytochemicals used in the management of pest fruit flies. Comparative behavioural, physiological and genomic approaches revealed that phytochemicals are mediating reproductive fitness by changing pheromonal compound males release and by making them physiologically more active. The possible mechanistic functions are that the phytochemicals act as a pheromone booster and as an energy supplement.

Capturing complex, non-linear team behaviours during competitive football performance

This study investigated changes in the complexity (magnitude and structure of variability) of the collective behaviours of association football teams during competitive performance. Raw positional data from an entire competitive match between two professional teams were obtained with the ProZone® tracking system. Five compound positional variables were used to investigate the collective patterns of performance of each team including: surface area, stretch index, team length, team width, and geometrical centre. Analyses involve the coefficient of variation (%CV) and approximate entropy (ApEn), as well as the linear association between both parameters. Collective measures successfully captured the idiosyncratic behaviours of each team and their variations across the six time periods of the match. Key events such as goals scored and game breaks (such as half time and full time) seemed to influence the collective patterns of performance. While ApEn values significantly decreased during each half, the %CV increased. Teams seem to become more regular and predictable, but with increased magnitudes of variation in their organisational shape over the natural course of a match.

Tethering for Selective Synthesis of 2,2′-Biphenols : the Acetal Method

2,2'-Biphenols are a large and diverse group of compounds with exceptional properties both as ligands and bioactive agents. Traditional methods for their synthesis by oxidative dimerisation are often problematic and lead to mixtures of ortho- and para-connected regioisomers. To compound these issues, an intermolecular dimerisation strategy is often inappropriate for the synthesis of heterodimers. The ‘acetal method’ provides a solution for these problems: stepwise tethering of two monomeric phenols enables heterodimer synthesis, enforces ortho regioselectivity and allows relatively facile and selective intramolecular reactions to take place. The resulting dibenzo[1,3]dioxepines have been analysed by quantum chemical calculations to obtain information about the activation barrier for ring flip between the enantiomers. Hydrolytic removal of the dioxepine acetal unit revealed the 2,2′-biphenol target.

Antibacterial anthranilic acid derivatives from Geijera parviflora

Five anthranilic acid derivatives, a mixture I of three new compounds 11′-hexadecenoylanthranilic acid (1), 9′-hexadecenoylanthranilic acid (2), and 7′-hexadecenoylanthranilic acid (3), as well as a new compound 9,12,15-octadecatrienoylanthranilic acid (4) together with a new natural product, hexadecanoylanthranilic acid (5), were isolated from Geijera parviflora Lindl. (Rutaceae). Their structures were elucidated by extensive spectroscopic measurements, and the positions of the double bonds in compounds 1-3 of the mixture I were determined by tandem mass spectrometry employing ozone-induced dissociation. The mixture I and compound 5 showed good antibacterial activity against several Gram-positive strains. © 2013 Elsevier B.V.

Why are there Different Age Related Trends for Different Chemicals?

Persistent organic pollutants (POPs) such as dioxins, PCBs, persistent organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs) as well as perfluorinated compounds (PFCs) and triclosan are ubiquitous in the human population. In Australia, we have pooled and subsequently analysed over 10 000 human serum samples for the determination of these chemicals by age group (0–0.5; 0.6–1; 1.1–1.5; 1.6–2; 2.1–2.5; 2.6–3; 3.1–3.5; 3.6–4; 4.1–6; 6.1–9; 9.1–12; 12.1–15; 16–30; 31–45; 46–60 and >60 years) and gender. The results of this analysis were then used to assess the trends of these different chemicals as a function of age, gender and to a lesser extent region. Our data demonstrate clear chemical specific age trends. In particular we demonstrate that for the traditional POPs there is an increase in body burden with age whereas the opposite is true for chemicals such as PBDEs. For PFCs we find chemical specific age trends that vary from compound to compound. For triclosan we show that no apparent age trend is observable. The results of the study and its implications to the collection and archiving of samples for retrospective analysis are discussed.

Identity, addressing, authenticity and audit requirements for trust in ERP, analytics and big/open data in a “Cloud” computing environment : a review and proposal

Enterprises, both public and private, have rapidly commenced using the benefits of enterprise resource planning (ERP) combined with business analytics and “open data sets” which are often outside the control of the enterprise to gain further efficiencies, build new service operations and increase business activity. In many cases, these business activities are based around relevant software systems hosted in a “cloud computing” environment. “Garbage in, garbage out”, or “GIGO”, is a term long used to describe problems in unqualified dependency on information systems, dating from the 1960s. However, a more pertinent variation arose sometime later, namely “garbage in, gospel out” signifying that with large scale information systems, such as ERP and usage of open datasets in a cloud environment, the ability to verify the authenticity of those data sets used may be almost impossible, resulting in dependence upon questionable results. Illicit data set “impersonation” becomes a reality. At the same time the ability to audit such results may be an important requirement, particularly in the public sector. This paper discusses the need for enhancement of identity, reliability, authenticity and audit services, including naming and addressing services, in this emerging environment and analyses some current technologies that are offered and which may be appropriate. However, severe limitations to addressing these requirements have been identified and the paper proposes further research work in the area.

Trust in merged ERP and open data schemes in the “Cloud”

Enterprise resource planning (ERP) systems are rapidly being combined with “big data” analytics processes and publicly available “open data sets”, which are usually outside the arena of the enterprise, to expand activity through better service to current clients as well as identifying new opportunities. Moreover, these activities are now largely based around relevant software systems hosted in a “cloud computing” environment. However, the over 50- year old phrase related to mistrust in computer systems, namely “garbage in, garbage out” or “GIGO”, is used to describe problems of unqualified and unquestioning dependency on information systems. However, a more relevant GIGO interpretation arose sometime later, namely “garbage in, gospel out” signifying that with large scale information systems based around ERP and open datasets as well as “big data” analytics, particularly in a cloud environment, the ability to verify the authenticity and integrity of the data sets used may be almost impossible. In turn, this may easily result in decision making based upon questionable results which are unverifiable. Illicit “impersonation” of and modifications to legitimate data sets may become a reality while at the same time the ability to audit any derived results of analysis may be an important requirement, particularly in the public sector. The pressing need for enhancement of identity, reliability, authenticity and audit services, including naming and addressing services, in this emerging environment is discussed in this paper. Some current and appropriate technologies currently being offered are also examined. However, severe limitations in addressing the problems identified are found and the paper proposes further necessary research work for the area. (Note: This paper is based on an earlier unpublished paper/presentation “Identity, Addressing, Authenticity and Audit Requirements for Trust in ERP, Analytics and Big/Open Data in a ‘Cloud’ Computing Environment: A Review and Proposal” presented to the Department of Accounting and IT, College of Management, National Chung Chen University, 20 November 2013.)

Tandem mass spectrometry of deprotonated iodothyronines

In order to assist with the development of more selective and sensitive methods for thyroid hormone analysis the \[M-H](-) anions of the iodothyronines T4, T3, rT3, (3,5)-T2 and the non-iodinated thyronine (TO) have been generated by negative ion electrospray mass spectrometry. Tandem mass spectra of these ions were recorded on a triple-quadrupole mass spectrometer and show a strong analogy with the fragmentation pathways of the parent compound, tyrosine. All iodothyronines also show significant abundances of the iodide anion in their tandem mass spectra, which represents an attractive target for multiple reaction monitoring (MRM) analysis, given that iodothyronines are the only iodine bearing endogenous molecules. Characteristic fragments are observed at m/z 359.7 and 604.5 for rT3 but are absent in the spectrum of T3, thus differentiating the two positional isomers. The striking difference in the fragmentation patterns of these regioisomeric species is attributed to the increased acidity of the phenol moiety in rT3 compared with T3. Copyright (C) 2005 John Wiley & Sons, Ltd.

Bayesian P-splines with a multiplicative term in EMG trace data

A method is proposed to describe force or compound muscle action potential (CMAP) trace data collected in an electromyography study for motor unit number estimation (MUNE). Experimental data was collected using incre- mental stimulation at multiple durations. However, stimulus information, vital for alternate MUNE methods, is not comparable for multiple duration data and therefore previous methods of MUNE (Ridall et al., 2006, 2007) cannot be used with any reliability. Hypothesised ring combinations of motor units are mod- elled using a multiplicative factor and Bayesian P-spline formulation. The model describes the process for force and CMAP in a meaningful way.

Poly[μ-aqua-bis(μ5-2,4-dichlorobenzoato)dipotassium

In the title compound, [K2(C7H3Cl2O2)2(H2O)]n, the potassium salt of 2,4-dichlorobenzoic acid, the repeating unit in the polymeric structure consists of two identical irregular KO6Cl complex units related by twofold rotational symmetry, linked by a bridging water molecule lying on the twofold axis. The coordination polyhedron about each K+ comprises a carboxyl O-atom and a Cl-atom donor from a bidentate chelate ligand interaction, four O-atom donors from a doubly bridging bidentate carboxyl (O,O')-chelate interaction and the water molecule. A two-dimensional layered coordination polymer structure lying parallel to (100) is generated through a series of conjoined cyclic bridges between K centres and is stabilized by water O-H...O(carboxyl) hydrogen-bonding interactions.

Poly[di-mu-aqua-bis{2-amino-4-nitrobenzoato)]-dirubidium

In the structure of title compound [Rb2(C7H5N2O4)2(H2O)2]n the asymmetric unit comprises two independent and different seven-coordinate Rb centres, one RbO7, the other RbO6N, with both having irregular stereochemistry. The RbO7 coordination comprises bridging oxygen donors from two water molecules, three carboxylate groups, and a nitro group, with one doubly bridging. The RbO6N coordination comprises the two bridging water molecules, one monodentate amine N donor, one carboxyl O donor and three O donors from nitro groups (one from the chelate bridge). The extension of the dinuclear unit gives a three-dimensional polymeric structure which is stabilized by both intra- and intermolecular amine N-H...O and water O-H...O hydrogen bonds to carboxyl and water O-atom acceptors, as well as a number of inter-ring \p--\p interactions [minimum ring centroid separation, 3.364(2) \%A]. This complex is both isostructural with the analogous Cs -nitroanthranilate monohydrate complex.

Proton-transfer and non-transfer compounds of the multi-purpose drug dapsone [4-(4-Aminophenylsulfonyl)aniline] with 3,5-dinitrosalicylic acid and 5-nitroisophthalic acid

The structures of the compounds from the reaction of the drug dapsone [4-(4-aminophenylsulfonyl)aniline] with 3,5-dinitrosalicylic acid, the salt hydrate [4-(4-aminohenylsulfonyl)anilinium 2-carboxy-4,6-dinitrophenolate monohydrate] (1) and the 1:1 adduct with 5-nitroisophthalic acid [4-(4-aminophenylsulfonyl)aniline 5-nitrobenzene-1,3-dicarboxylic acid] (2) have been determined. Crystals of 1 are triclinic, space group P-1, with unit cell dimensions a = 8.2043(3), b = 11.4000(6), c = 11.8261(6)Å, α = 110.891(5), β = 91.927(3), γ = 98.590(4)deg. and Z = 4. Compound 2 is orthorhombic, space group Pbcn, with unit cell dimensions a = 20.2662(6), b = 12.7161(4), c = 15.9423(5)Å and Z = 8. In 1, intermolecular analinium N-H…O and water O-H…O and O-H…N hydrogen-bonding interactions with sulfone, carboxyl, phenolate and nitro O-atom and aniline N-atom acceptors give a two-dimensional layered structure. With 2, the intermolecular interactions involve both aniline N-H…O and carboxylic acid O-H…O and O-H…N hydrogen bonds to sulfone, carboxyl, nitro and aniline acceptors, giving a three-dimensional network structure. In both structures π--π aromatic ring associations are present.

UNIFOLIATA regulates leaf and flower morphogenesis in pea

Background The vegetative phenotype of the pea mutant unifoliata (uni) is a simplification of the wild-type compound leaf to a single leaflet. Mutant uni plants are also self-sterile and the flowers resemble known floral meristem and organ identity mutants. In Antirrhinum and Arabidopsis, mutations in the floral meristem identity gene FLORICAULA/LEAFY (FLO/LFY) affect flower development alone, whereas the tobacco FLO/LFY homologue, NFL, is expressed in vegetative tissues, suggesting that NFL specifies determinacy in the progenitor cells for both flowers and leaves. In this paper, we characterised the pea homologue of FLO/LFY. Results The pea cDNA homologue of FLO/LFY, PEAFLO, mapped to the uni locus in recombinant-inbred mapping populations and markers based on PEAFLO cosegregated with uni in segregating sibling populations. The characterisation of two spontaneous uni mutant alleles, one containing a deletion and the other a point mutation in the PEAFLO coding sequences, predicted that PEAFLO corresponds to UNI and that the mutant vegetative phenotype was conferred by the defective PEAFLO gene. Conclusions The uni mutant demonstrates that there are shared regulatory processes in the morphogenesis of leaves and flowers and that floral meristem identity genes have an extended role in plant development. Pleiotropic regulatory genes such as UNI support the hypothesis that leaves and flowers derive from a common ancestral sporophyll-like structure. The regulation of indeterminacy during leaf and flower morphogenesis by UNI may reflect a primitive function for the gene in the pre-angiosperm era.