The inter-relationships between ovarian-independent growth, tumorigenicity, invasiveness and antioestrogen resistance in the malignant progression of human breast cancer

Among the processes contributing to the progressive acquisition of the highly malignant phenotype in breast cancer are ovarian-independent growth, antioestrogen resistance and increased metastatic potential. We have previously observed that increased invasiveness and development of ovarian-independent growth occur independently. In an attempt to define the inter-relationships between these processes further, we have compared the phenotypes of ovarian-independent, invasive and antioestrogen-resistant sublines of the ovarian-dependent human breast cancer cell line MCF-7. Cells acquiring ovarian-independent growth can retain sensitivity to anti-oestrogens. One clone of MCF-7 cells selected for stable antioestrogen resistance has become non-tumorigenic but its invasive potential remains unaltered. Thus, acquisitions of some characteristics of the progressed phenotype can occur independently. This phenomenon of independent parameters in phenotypic progression could partly explain the considerable intra- and intertumour heterogeneity characteristic of breast tumours.

Resistance of microbial populations in DDT-contaminated and uncontaminated soils

One DDT-contaminated soil and two uncontaminated soils were used to enumerate DDT-resistant microbes (bacteria, actinomycetes and fungi) by using soil dilution agar plates in media either with 150 μg DDT ml -1 or without DDT at different temperatures (25, 37 and 55°C). Microbial populations in this study were significantly (p<0.001) affected by DDT in the growth medium. However, the numbers of microbes in long-term contaminated and uncontaminated soils were similar, presumably indicating that DDT-resistant microbes had developed over a long time exposure. The tolerance of isolated soil microbes to DDT varied in the order fungi>actinomycetes>bacteria. Bacteria from contaminated soil were more resistant to DDT than bacteria from uncontaminated soils. Microbes isolated at different temperatures also demonstrated varying degrees of DDT resistance. For example, bacteria and actinomycetes isolated at all incubation temperatures were sensitive to DDT. Conversely fungi isolated at all temperatures were unaffected by DDT.

DDT resistance and transformation by different microbial strains isolated from DDT-contaminated soils and compost materials

Bioremediation is a potential option to treat 1, 1, 1-trichloro-2, 2 bis (4-chlorophenyl) ethane (DDT) contaminated sites. In areas where suitable microbes are not present, the use of DDT resistant microbial inoculants may be necessary. It is vital that such inoculants do not produce recalcitrant breakdown products e.g. 1, 1-dichloro-2, 2-bis (4-chlorophenyl) ethylene (DDE). Therefore, this work aimed to screen DDT-contaminated soil and compost materials for the presence of DDT-resistant microbes for use as potential inoculants. Four compost amended soils, contaminated with different concentrations of DDT, were used to isolate DDT-resistant microbes in media containing 150 mg I -1 DDT at three temperatures (25, 37 and 55°C). In all soils, bacteria were more sensitive to DDT than actinomycetes and fungi. Bacteria isolated at 55°C from any source were the most DDT sensitive. However DDT-resistant bacterial strains showed more promise in degrading DDT than isolated fungal strains, as 1, 1-dichloro 2, 2-bis (4-chlorophenyl) ethane (DDD) was a major bacterial transformation product, while fungi tended to produce more DDE. Further studies on selected bacterial isolates found that the most promising bacterial strain (Bacillus sp. BHD-4) could remove 51% of DDT from liquid culture after 7 days growth. Of the amount transformed, 6% was found as DDD and 3% as DDE suggesting that further transformation of DDT and its metabolites occurred.

A Bayesian hurdle model for analysis of an insect resistance monitoring database

Motivated by the analysis of the Australian Grain Insect Resistance Database (AGIRD), we develop a Bayesian hurdle modelling approach to assess trends in strong resistance of stored grain insects to phosphine over time. The binary response variable from AGIRD indicating presence or absence of strong resistance is characterized by a majority of absence observations and the hurdle model is a two step approach that is useful when analyzing such a binary response dataset. The proposed hurdle model utilizes Bayesian classification trees to firstly identify covariates and covariate levels pertaining to possible presence or absence of strong resistance. Secondly, generalized additive models (GAMs) with spike and slab priors for variable selection are fitted to the subset of the dataset identified from the Bayesian classification tree indicating possibility of presence of strong resistance. From the GAM we assess trends, biosecurity issues and site specific variables influencing the presence of strong resistance using a variable selection approach. The proposed Bayesian hurdle model is compared to its frequentist counterpart, and also to a naive Bayesian approach which fits a GAM to the entire dataset. The Bayesian hurdle model has the benefit of providing a set of good trees for use in the first step and appears to provide enough flexibility to represent the influence of variables on strong resistance compared to the frequentist model, but also captures the subtle changes in the trend that are missed by the frequentist and naive Bayesian models.

Should we tailor standardize exercise interventions to suit differing menopausal status?

The article by Kretzschmar et al in this issue of Menopause details a study investigating the effect of a mild-intensity aerobic exercise training program on markers of mortality risk in both pre- and post-menopausal African American women. The findings of this study showed that aerobic exercise training was successful in improving some markers of cardiovascular disease and mortality in post-menopausal women. The premise of this study, however, does suggest that increased exercise intensity may be required in post-menopausal women as opposed to pre menopausal women to achieve the same decreased changes in CVD markers. The outcome of the study is thus of interest to the readers of Menopause and to all those who provide health care to postmenopausal women, as they suggest that higher levels of exercise intensity or perhaps additional interventions may need to be considered in this population to further decrease mortality risk. The study therefore, has greater implications than simply the suggesting of tailoring exercise interventions generally, rather, the publication highlights the importance of prescribing exercise as medicine in a tailored fashion for women depending on their menopausal status.

Effect of Coulomb blockade, gold resistance, and thermal expansion on the electrical resistance of ultrathin gold films

Controlling the electrical resistance of granular thin films is of great importance for many applications, yet a full understanding of electron transport in such films remains a major challenge. We have studied experimentally and by model calculations the temperature dependence of the electrical resistance of ultrathin gold films at temperatures between 2 K and 300 K. Using sputter deposition, the film morphology was varied from a discontinuous film of weakly coupled meandering islands to a continuous film of strongly coupled coalesced islands. In the weak-coupling regime, we compare the regular island array model, the cotunneling model, and the conduction percolation model with our experimental data. We show that the tunnel barriers and the Coulomb blockade energies are important at low temperatures and that the thermal expansion of the substrate and the island resistance affect the resistance at high temperatures. At low temperatures our experimental data show evidence for a transition from electron cotunneling to sequential tunneling but the data can also be interpreted in terms of conduction percolation. The resistivity and temperature coefficient of resistance of the meandering gold islands are found to resemble those of gold nanowires. We derive a simple expression for the temperature at which the resistance changes from non-metal-like behavior into metal-like behavior. In the case of strong island coupling, the total resistance is solely determined by the Ohmic island resistance.

Fire resistance rating of light gauge steel frame walls exposed to realistic design fires : a review and development of time equivalent approach

This paper presents the details of research undertaken on the development of an energy based time equivalent approach for light gauge steel frame (LSF) walls. This research utilized an energy based time equivalent approach to obtain the fire resistance ratings (FRR) of LSF walls exposed to realistic design fires with respect to standard fire exposure [1]. It is based on the equal area concept of fire severity and relates to the amount of energy transferred to the member. The proposed method was used to predict the fire resistance of single and double plasterboard lined and externally insulated LSF walls. The predicted fire resistance ratings were compared with the results from finite element analyses and fire design rules for three different wall configurations. This paper presents the review of the available time equivalent approaches and the development of energy based time equivalent approach for the prediction of fire resistance ratings of LSF walls exposed to realistic design fires.

BRAF inhibitor therapy for melanoma, thyroid and colorectal cancers : development of resistance and future prospects

BRAF is a major oncoprotein and oncogenic mutations in BRAF are found in a significant number of cancers, including melanoma, thyroid cancer, colorectal cancer and others. Consequently, BRAF inhibitors have been developed as treatment options for cancers with BRAF mutations which have shown some success in improving patient outcomes in clinical trials. Development of resistance to BRAF kinase inhibitors is common, however, and overcoming this resistance is an area of significant concern for clinicians, patients and researchers alike. In this review, we identify the mechanisms of BRAF kinase inhibitor resistance and discuss the implications for strategies to overcome this resistance in the context of new approaches such as multi-kinase targeted therapies and emerging RNA interference based technologies.

Legislative impact on the mortgagee’s exercise of power of sale : the need for rationalisation

Throughout Australia, regulation of the power of sale is highly inconsistent. In response to the uncertain nature of the mortgagee’s duty at common law, many legislatures have intervened. As a result, there has been a proliferation of statutory formula conferring varying degrees of protection on mortgagors. The differences in approach indicate a lack of consensus as to the best method of regulation. This article exposes the extent of the inconsistency and provides a comparative assessment of the various provisions with reference to the policy concerns that underpin legislative intervention. The article identifies a number of deficiencies associated with existing provisions and concludes that mortgagees and mortgagors alike would benefit from improved clarity and consistency. To that end, the article proposes a model provision that seeks to address the deficiencies identified.

Virtual resistance based active damping solution for constant power instability in AC microgrids

With ever-increasing share of power electronic loads constant power instability is becoming a significant issue in microgrids, especially when they operate in the islanding mode. Transient conditions like resistive load-shedding or sudden increase of constant power loads (CPL) might destabilize the whole system. Modeling and stability analysis of AC microgrids with CPLs have already been discussed in literature. However, no effective solutions are provided to stabilize this kind of system. Therefore, this paper proposes a virtual resistance based active damping method to eliminate constant power instability in AC microgrids. Advantages and limitations of the proposed method are also discussed in detail. Simulation results are presented to validate the proposed active damping solution.

The effect of ß-alanine on buffering capacity and exercise performance during and following high-intensity exercise in healthy males

Introduction Intense exercise induced acidosis occurs from the accumulation of hydrogen ions as by-products of anaerobic metabolism. Oral ingestion of ß-alanine, a limiting precursor of the intracellular physiochemical buffer carnosine in skeletal muscle, may counteract any detrimental effect of acidosis and benefit performance. The aim of this study was to investigate the effect of ß-alanine as an ergogenic aid during high intensity exercise performance in healthy males. Methods Five males ingested either ß-alanine (BAl) (4.8 g.d-1 for 4wk, then 6.4 g.d-1 for 2wk) or placebo (Pl) (CaCO3) in a crossover design with 6 wk washout between. Following supplementation, participants performed two different intense exercise protocols over consecutive days. On the first day a repeated sprint ability (RSA) test of 5 x 6s, with 24s rest periods, was performed. On the second day a cycling capacity test measuring the time to exhaustion (TTE) was performed at 110% of their max workload achieved in a pre supplementation max test (CCT110%). Non-invasive quantification of carnosine, prior to, and following each supplementation, with magnetic resonance spectrometry was performed in the soleus and gastrocnemius. Time to fatigue (CCT110%), peak and mean power (RSA), blood pH, and plasma lactate were measured. Results Muscle carnosine concentration was not different prior to ß-alanine supplementation and increased 18% in the soleus and 26% in the gastrocnemius, respectively with 6 wk supplementation. There was no difference in the measured performance variables during the RSA test (peak and average power output). TTE during the CCT110% was significantly enhanced following the ingestion of BAl (155s ± 19.03) compared to Pl (134s ± 26.16). No changes were observed in blood pH during either exercise protocol and during the recovery from exercise. Plasma lactate in the BAl condition was significantly higher than Pl only from the 15th minute following exercise during the CCT110%. FIG. 1: Changes in carnosine concentration in the gastrocnemius prior and post 6 week chronic supplementation of placebo and β-alanine. Values expressed as mean.* p<0.05 from Pl at 6 weeks, # p<0.05 from pre supplementation. Conclusion/Discussion Greater muscle carnosine content following 6wk supplementation of ß-alanine enhanced the potential for intracellular buffering capacity. However, this only translated into enhanced performance during the CCT110% high intensity cycling exercise protocol, with no change observed during the RSA test. No differences in post exercise and recovery plasma lactates and blood pH, indicates that 6wks ß-alanine supplementation has no effect on anaerobic metabolism during multiple bout high intensity exercise. Changes in plasma lactate during recovery supports that ß-alanine supplementation may affect anaerobic metabolism however during single bout high intensity.

The effect of ß-alanine on buffering capacity and exercise performance during and following high-intensity exercise in healthy males

Intense exercise induced acidosis occurs after accumulation of hydrogen ions as by-products of anaerobic metabolism. Oral ingestion of ß-alanine, a limiting precursor of the intracellular physiochemical buffer carnosine in skeletal muscle, may counteract detrimental effects of acidosis and benefit performance. This study aimed to investigate the effect of ß-alanine as an ergogenic aid during high intensity exercise performance. Five healthy males ingested either ß-alanine or placebo (Pl) (CaCO3) in a crossover design with 6 wk washout between. Participants performed two different intense exercise protocols over consecutive days. On the first day a repeated sprint ability (RSA) test was performed. On the second day a cycling capacity test measuring the time to exhaustion (TTE) was performed at 110% of maximum workload achieved in a pre supplementation max test (CCT110%). Non-invasive quantification of carnosine, prior to, and following each supplementation, with in vivo magnetic resonance spectrometry was performed in the soleus and gastrocnemius muscle. Time to fatigue (CCT110%), peak and mean power (RSA), blood pH, and plasma lactate were measured. Muscle carnosine concentration was not different prior to ß-alanine supplementation and increased 18% in the soleus and 26% in the gastrocnemius, respectively after supplementation. There was no difference in the measured performance variables during the RSA test (peak and average power output). TTE during the CCT110% was significantly enhanced following the ingestion of BAl (155s ± 19.03) compared to Pl (134s ± 26.16). No changes were observed in blood pH during either exercise protocol and during the recovery from exercise. Plasma lactate after BAI was significantly higher than Pl only from the 15th minute following exercise during the CCT110%. Greater muscle carnosine content following 6wk supplementation of ß-alanine enhanced the potential for intracellular buffering capacity. This translated into enhanced performance during the CCT110% high intensity cycling exercise protocol but not during the RSA test. The lack of change in plasma lactate or blood pH indicates that 6wks ß-alanine supplementation has no effect on anaerobic metabolism during multiple-bout high-intensity exercise. Changes measured in plasma lactate during recovery support the hypothesis that ß-alanine supplementation may affect anaerobic metabolism particularly during single bout high intensity.

Artemisinin resistance in Plasmodium falciparum : a process linked to dormancy?

Artemisinin (ART) based combination therapy (ACT) is used as the first line treatment of uncomplicated falciparum malaria in over 100 countries and is the cornerstone of malaria control and elimination programs in these areas. However, despite the high potency and rapid parasite killing action of ART derivatives there is a high rate of recrudescence associated with ART monotherapy and recrudescence is not uncommon even when ACT is used. Compounding this problem are reports that some parasites in Cambodia, a known foci of drug resistance, have decreased in vivo sensitivity to ART. This raises serious concerns for the development of ART resistance in the field even though no major phenotypic and genotypic changes have yet been identified in these parasites. In this article we review available data on the characteristics of ART, its effects on Plasmodium falciparum parasites and present a hypothesis to explain the high rate of recrudescence associated with this potent class of drugs and the current enigma surrounding ART resistance.

Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives.