BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

The rapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The importance of mosquito behavioural adaptations to malaria control in Africa

Over the past decade the use of long-lasting insecticidal nets (LLINs), in combination with improved drug therapies, indoor residual spraying (IRS) and better health infrastructure, has helped reduce malaria in many African countries for the first time in a generation. However, insecticide resistance in the vector is an evolving threat to these gains. We review emerging and historical data on behavioural resistance in response to LLINs and IRS. Overall the current literature suggests behavioural and species changes may be emerging, but the data are sparse and, at times unconvincing. However, preliminary modelling has demonstrated that behavioural resistance could have significant impacts on the effectiveness of malaria control. We propose seven recommendations to improve understanding of resistance in malaria vectors. Determining the public health impact of physiological and behavioural insecticide resistance is an urgent priority if we are to maintain the significant gains made in reducing malaria morbidity and mortality.

Inflammation, hepatic enzymes and resistance training in individuals with metabolic risk factors

AIMS: Increases in inflammatory markers, hepatic enzymes and physical inactivity are associated with the development of the metabolic syndrome (MetS). We examined whether inflammatory markers and hepatic enzymes are correlated with traditional risk factors for MetS and studied the effects of resistance training (RT) on these emerging risk factors in individuals with a high number of metabolic risk factors (HiMF, 2.9 +/- 0.8) and those with a low number of metabolic risk factors (LoMF, 0.5 +/- 0.5). METHODS: Twenty-eight men and 27 women aged 50.8 +/- 6.5 years (mean +/- sd) participated in the study. Participants were randomized to four groups, HiMF training (HiMFT), HiMF control (HiMFC), LoMF training (LoMFT) and LoMF control (LoMFC). Before and after 10 weeks of RT [3 days/week, seven exercises, three sets with intensity gradually increased from 40-50% of one repetition maximum (1RM) to 75-85% of 1RM], blood samples were obtained for the measurement of pro-inflammatory cytokines, C-reactive protein (CRP), gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT). RESULTS: At baseline, HiMF had higher interleukin-6 (33.9%), CRP (57.1%), GGT (45.2%) and ALT (40.6%) levels, compared with LoMF (all P < 0.05). CRP, GGT and ALT correlated with the number of risk factors (r = 0.48, 0.51 and 0.57, respectively, all P < 0.01) and with other anthropometric and clinical measures (r range from 0.26 to 0.60, P < 0.05). RT did not significantly alter inflammatory markers or hepatic enzymes (all P > 0.05). CONCLUSIONS: HiMF was associated with increased inflammatory markers and hepatic enzyme concentrations. RT did not reduce inflammatory markers and hepatic enzymes in individuals with HiMF.

The time course of in vivo recovery of transverse strain in high-stress tendons following exercise

Objective To evaluate the time course of the recovery of transverse strain in the Achilles and patellar tendon following a bout of resistance exercise. Methods Seventeen healthy adults underwent sonographic examination of the right patellar (n=9) and Achilles (n=8) tendons immediately prior to and following 90 repetitions of weight-bearing quadriceps and gastrocnemius-resistance exercise performed against an effective resistance of 175% and 250% body weight, respectively. Sagittal tendon thickness was determined 20 mm from the enthesis and transverse strain, as defined by the stretch ratio, was repeatedly monitored over a 24 h recovery period. Results Resistance exercise resulted in an immediate decrease in Achilles (t7=10.6, p<0.01) and patellar (t8=8.9, p<0.01) tendon thickness, resulting in an average transverse stretch ratio of 0.86±0.04 and 0.82±0.05, which was not significantly different between tendons. The magnitude of the immediate transverse strain response, however, was reduced with advancing age (r=0.63, p<0.01). Recovery in transverse strain was prolonged compared with the duration of loading and exponential in nature. The average primary recovery time was not significantly different between the Achilles (6.5±3.2 h) and patellar (7.1±3.2 h) tendons. Body weight accounted for 62% and 64% of the variation in recovery time, respectively. Conclusions Despite structural and biochemical differences between the Achilles and patellar tendon, the mechanisms underlying transverse creep recovery in vivo appear similar and are highly time dependent. These novel findings have important implications concerning the time required for the mechanical recovery of high-stress tendons following an acute bout of exercise.

Something’s coming, something good: Identifying TPACK competence in pre-service teachers’ analyses of learning objects

There is a song at the beginning of the musical, West Side Story, where the character Tony sings that “something’s coming, something good.” The song is an anthem of optimism, brimming with promise. This paper is about the long-held promise of information and communication technology (ICT) to transform teaching and learning, to modernise the learning environment of the classroom, and to create a new digital pedagogy. But much of our experience to date in the schooling sector tells more of resistance and reaction than revolution, of more of the same but with a computer in the corner and of ICT activities as unwelcome time-fillers/time-wasters. Recently, a group of pre-service teachers in a postgraduate primary education degree in an Australian university were introduced to learning objects in an ICT immersion program. Their analyses and related responses, as recorded in online journals, have here been interpreted in terms of TPACK (Technological Pedagogical and Content Knowledge). Against contemporary observation, these students generally displayed high levels of competence and highly positive dispositions of students to the integration of ICT in their future classrooms. In short, they displayed the same optimism and confidence as the fictional “Tony” in believing that something good was coming.

Consecutive bouts of diverse contractile activity alter acute responses in human skeletal muscle

We examined acute molecular responses in skeletal muscle to divergent exercise stimuli by combining consecutive bouts of resistance and endurance exercise. Eight men [22.9 ± 6.3 yr, body mass of 73.2 ± 4.5 kg, peak O2 uptake (V?O2peak) of 54.0 ± 5.7 ml·kg-1·min-1] were randomly assigned to complete trials consisting of either resistance exercise (8 x 5 leg extension, 80% 1 repetition maximum) followed by a bout of endurance exercise (30 min cycling, 70% V?O2peak) or vice versa. Muscle biopsies were obtained from the vastus lateralis at rest, 15 min after each exercise bout, and after 3 h of passive recovery to determine early signaling and mRNA responses. Phosphorylation of Akt and Akt1Ser473 were elevated 15 min after resistance exercise compared with cycling, with the greatest increase observed when resistance exercise followed cycling (?55%; P < 0.01). TSC2-mTOR-S6 kinase phosphorylation 15 min after each bout of exercise was similar regardless of the exercise mode. The cumulative effect of combined exercise resulted in disparate mRNA responses. IGF-I mRNA content was reduced when cycling preceded resistance exercise (-42%), whereas muscle ring finger mRNA was elevated when cycling was undertaken after resistance exercise (?52%; P < 0.05). The hexokinase II mRNA level was higher after resistance cycling (?45%; P < 0.05) than after cycling-resistance exercise, whereas modest increases in peroxisome proliferator-activated receptor gamma coactivator-1? mRNA did not reveal an order effect. We conclude that acute responses to diverse bouts of contractile activity are modified by the exercise order. Moreover, undertaking divergent exercise in close proximity influences the acute molecular profile and likely exacerbates acute "interference".

Recovery of transverse strain in high–stress tendons following exercise

Background. This study evaluated the time course of recovery of transverse strain in the Achilles and patellar tendons following a bout of resistance exercise. Methods. Seventeen healthy adults underwent sonographic examination of the right patellar (n = 9) or Achilles (n = 8) tendons immediately prior to and following 90 repetitions of weight–bearing exercise. Quadriceps and gastrocnemius exercise were performed against an effective resistance of 175% and 250% body weight, respectively. Sagittal tendon thickness was determined 20 mm from the tendon enthesis and transverse strain was repeatedly monitored over a 24 hour recovery period. Results. Resistance exercise resulted in an immediate decrease in Achilles (t7 = 10.6, P<.01) and patellar (t8 = 8.9, P<.01) tendon thickness, resulting in an average transverse strain of 0.14 ± 0.04 and 0.18 ± 0.05. While the average strain was not significantly different between tendons, older age was associated with a reduced transverse strain response (r=0.63, P<.01). Recovery of transverse strain, in contrast, was prolonged compared with the duration of loading and exponential in nature. The mean primary recovery time was not significantly different between Achilles (6.5 ± 3.2 hours) and patellar (7.1 ± 3.2 hours) tendons and body weight accounted for 62% and 64% of the variation in recovery time, respectively. Discussion. Despite structural and biochemical differences between the Achilles and patellar tendons [1], the mechanisms underlying transverse creep–recovery in vivo appear similar and are highly time dependent. Primary recovery required about 7 hours in healthy tendons, with full recovery requiring up to 24 hours. These in vivo recovery times are similar to those reported for axial creep recovery of the vertebral disc in vitro [2], and may be used clinically to guide physical activity to rest ratios in healthy adults. Optimal ratios for high–stress tendons in clinical populations, however, remain unknown and require further attention in light of the knowledge gained in this study.

Resistance is feral : digital culture, community arts, and the new cultural gatekeepers

The Community Arts sector in Australia has a history of resistance. It has challenged hegemonic culture through facilitating grassroots creative production, contesting notions of artistic processes, and the role of the artist in society. This paper examines this penchant for resistance through the lens of contemporary digital culture, to establish that the sector is continuing to challenge dominant forms of cultural control. It then proposes that this enthusiasm and activity lacks ethical direction, describing it as feral to encompass the potential of current practices, while highlighting how a level of taming is needed in order to develop ethical approaches.

The Yd2 resistance to barley yellow dwarf virus is effective in barley plants but not in their leaf protoplasts

The Yd2 gene for “resistance” to barley yellow dwarf virus (BYDV) has been widely used in barley (Hordeum vulgare). We have tested Australian isolates of BYDV of varying severity against barley genotypes with and without the Yd2 gene and report here a positive relationship between symptoms and virus levels determined by ELISA. Cultivar Shannon is the result of backcrossing the resistant line CI 3208 to cultivar Proctor, a susceptible line. It appears to be intermediate in reaction to BYDV between Proctor and CI 3208, although it carries the major gene, Yd2. Unlike the whole plant studies, no significant differences were observed with regard to the ability of protoplasts derived from these various genotypes to support BYDV replication. It is therefore demonstrated for the first time that the Yd2 gene is not among the small number of resistance genes which are effective against virus replication in isolated protoplasts.

Targeting nuclear factor-kappa B to overcome resistance to chemotherapy

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

Effect of exercise training on skeletal muscle cytokine expression in the elderly

Aging is associated with increased circulating pro-inflammatory and lower anti-inflammatory cytokines. Exercise training, in addition to improving muscle function, reduces these circulating pro-inflammatory cytokines. Yet, few studies have evaluated changes in the expression of cytokines within skeletal muscle after exercise training. The aim of the current study was to examine the expression of cytokines both at rest and following a bout of isokinetic exercise performed before and after 12 weeks of resistance exercise training in young (n = 8, 20.3 ± 0.8 yr) and elderly men (n = 8, 66.9 ± 1.6 yr). Protein expression of various cytokines was determined in muscle homogenates. The expression of MCP-1, IL-8 and IL-6 (which are traditionally classified as ‘pro-inflammatory’) increased substantially after acute exercise. By contrast, the expression of the anti-inflammatory cytokines IL-4, IL-10 and IL-13 increased only slightly (or not at all) after acute exercise. These responses were not significantly different between young and elderly men, either before or after 12 weeks of exercise training. However, compared with the young men, the expression of pro-inflammatory cytokines 2 h post exercise tended to be greater in the elderly men prior to training. Training attenuated this difference. These data suggest that the inflammatory response to unaccustomed exercise increases with age. Furthermore, regular exercise training may help to normalize this inflammatory response, which could have important implications for muscle regeneration and adaptation in the elderly.

Anti-proliferative and cytotoxic activity of pentadactylin isolated from Leptodactylus labyrinthicus on melanoma cells

Nowadays, the emergence of resistance to the current available chemotherapeutic drugs by cancer cells makes the development of new agents imperative. The skin secretion of amphibians is a natural rich source of antimicrobial peptides (AMP), and researchers have shown that some of these wide spectrum molecules are also toxic to cancer cells. The aim of this study was to verify a putative anticancer activity of the AMP pentadactylin isolated for the first time from the skin secretion of the frog Leptodactylus labyrinthicus and also to study its cytotoxic mechanism to the murine melanoma cell line B16F10. The results have shown that pentadactylin reduces the cell viability of B16F10 cells in a dose-dependent manner. It was also cytotoxic to normal human fibroblast cells; nevertheless, pentadactylin was more potent in the first case. The studies of action mechanism revealed that pentadactylin causes cell morphology alterations (e.g., round shape and shrinkage morphology), membrane disruption, DNA fragmentation, cell cycle arrest at the S phase, and alteration of mitochondrial membrane potential, suggesting that B16F10 cells die by apoptosis. The exact mechanism that causes reduction of cell viability and cytotoxicity after treatment with pentadactylin is still unknown. In conclusion, as cancer cells become resilient to death, it is worthwhile the discovery of new drugs such as pentadactylin that induces apoptosis.

An investigation into resistance practices at an SME consultancy

Purpose Prior research emphasizes that organizational founders have a good deal of influence in organizational development and, where ICTs are involved, a generic strategy is usually deployed by managers in order to deal with any resistance that might occur. Cognisant of this, we investigated the role played by a Managing Director of an SME consultancy in an ICT project associated with organizational development. Design/methodology/approach This study is based on an ethnography of a ICT related change management initiative which, theoretically, takes into account though from the social shaping of technology – speifically the idea that technologies in their broadest sense are subject to ongoing work beyond the design stage. Findings We argue that Markus’ Interaction Theory of resistance still has relevance today and we extend it by emphasizing the problem of homogenizing users and downplaying their ability to appropriate resistance strategies in situ. Research limitations/implications Our study is based upon one group of individual’s experiences. Further case studies of resistance success are required which further highlight how such this is achieved and why. Practical implications Those engaged with organisational development projects need to be better educated as to the reasons for resistance, particularly positive ones, and the methods by which this might take place. Originality/value This study conceptualises strategies for ‘overcoming’ resistance as managerial technologies. Conceptualising them in this way, shows the deployement of such technologies to be a complicated and active process where the audience for such things are involved in how they are received and appropriated to suite differing agendas.

Resistance or covert infection : baculovirus studies re-examined

Recently, Boots & Begon (1993) described the development of resistance to granulosis virus (GV) (Baculoviridae) infection in the moth Plodia interpunctella, following prolonged exposure to virus in laboratory cultures. Resistant insects exhibited reduced fitness in other respects, namely slower development and reduced egg viability, compared to control insects. These results were interpreted as pleiotropic effects of selection at the loci controlling resistance. Similar results have been described in a previous study: Fuxa & Richter (1989) used artificial selection to increase resistance to nuclear polyhedrasis virus (NPV) (Baculoviridae) infection in the moth Spodoptera frugiperda. The resulting gain in resistance they interpreted as the result of an increase in the frequency of alleles conferring resistance. Again, resistant insects exhibited maladaptive traits compared to controls, including a shorter adult life span, reduced number of eggs and reduced egg viability. In both studies the suggestion is made that selection against maladaptive traits will result in a decline in resistance, once selection for resistance is removed. Boots & Begon (1993) described a decrease in development time (towards that of control insects) within two generations of removing selection for resistance. Fuxa & Richter (1989) describe a decrease in resistance, so that within two generations of relaxing selection, previously resistant lines were not significantly more resistant than control insects. . .