Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide : Phase I clinical trial of three dosing schedules in patients with solid malignancies

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25 mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration. © 2006 Elsevier Ltd. All rights reserved.

Nuclear gene silencing directs reception of long-distance mRNA silencing in Arabidopsis

In plants, silencing of mRNA can be transmitted from cell to cell and also over longer distances from roots to shoots. To investigate the long-distance mechanism, WT and mutant shoots were grafted onto roots silenced for an mRNA. We show that three genes involved in a chromatin silencing pathway, NRPD1a encoding RNA polymerase IVa, RNA-dependent RNA polymerase 2 (RDR2), and DICER-like 3 (DCL3), are required for reception of long-distance mRNA silencing in the shoot. A mutant representing a fourth gene in the pathway, argonaute4 (ago4), was also partially compromised in the reception of silencing. This pathway produces 24-nt siRNAs and resulted in decapped RNA, a known substrate for amplification of dsRNA by RDR6. Activation of silencing in grafted shoots depended on RDR6, but no 24-nt siRNAs were detected in mutant rdr6 shoots, indicating that RDR6 also plays a role in initial signal perception. After amplification of decapped transcripts, DCL4 and DCL2 act hierarchically as they do in antiviral resistance to produce 21- and 22-nt siRNAs, respectively, and these guide mRNA degradation. Several dcl genotypes were also tested for their capacity to transmit the mobile silencing signal from the rootstock. dcl1-8 and a dcl2 dcl3 dcl4 triple mutant are compromised in micro-RNA and siRNA biogenesis, respectively, but were unaffected in signal transmission. © 2007 by The National Academy of Sciences of the USA.

On the role of RNA silencing in the pathogenicity and evolution of viroids and viral satellites

Viroids and most viral satellites have small, noncoding, and highly structured RNA genomes. How they cause disease symptoms without encoding proteins and why they have characteristic secondary structures are two longstanding questions. Recent studies have shown that both viroids and satellites are capable of inducing RNA silencing, suggesting a possible role of this mechanism in the pathology and evolution of these subviral RNAs. Here we show that preventing RNA silencing in tobacco, using a silencing suppressor, greatly reduces the symptoms caused by the Y satellite of cucumber mosaic virus. Furthermore, tomato plants expressing hairpin RNA, derived from potato spindle tuber viroid, developed symptoms similar to those of potato spindle tuber viroid infection. These results provide evidence suggesting that viroids and satellites cause disease symptoms by directing RNA silencing against physiologically important host genes. We also show that viroid and satellite RNAs are significantly resistant to RNA silencing-mediated degradation, suggesting that RNA silencing is an important selection pressure shaping the evolution of the secondary structures of these pathogens.

Virus resistance and gene silencing in plants can be induced by simultaneous expression of sense and antisense RNA

Many examples of extreme virus resistance and posttranscriptional gene silencing of endogenous or reporter genes have been described in transgenic plants containing sense or antisense transgenes. In these cases of either cosuppression or antisense suppression, there appears to be induction of a surveillance system within the plant that specifically degrades both the transgene and target RNAs. We show that transforming plants with virus or reporter gene constructs that produce RNAs capable of duplex formation confer virus immunity or gene silencing on the plants. This was accomplished by using transcripts from one sense gene and one antisense gene colocated in the plant genome, a single transcript that has self-complementarity, or sense and antisense transcripts from genes brought together by crossing. A model is presented that is consistent with our data and those of other workers, describing the processes of induction and execution of posttranscriptional gene silencing.

Comparison of the coat protein, movement protein and RNA polymerase gene sequences of Australian, Chinese, and American isolates of barley yellow dwarf virus transmitted by Rhopalosiphum padi

Barley yellow dwarf luteovirus-GPV (BYDV-GPV) is a common problem in Chinese wheat crops but is unrecorded elsewhere. A defining characteristic of GPV is its capacity to be transmitted efficiently by both Schizaphis graminum and Rhopaloshiphum padi. This dual aphid species transmission contrasts with those of BYDV-RPV and BYDV-SGV, globally distributed viruses, which are efficiently transmitted only by Rhopaloshiphum padi and Schizaphis graminum respectively. The viral RNA sequences encoding the coat protein (22K) gene, the movement protein (17K) gene, the region surrounding the conserved GDD motif of the polymerase gene and the intergenic sequences between these genes were determined for GPV and an Australian isolate of BYDV-RPV (RPVa). In all three genes, the sequences of GPV and RPVa were more similar to those of an American isolate of BYDV-RPV (RPVu) than to any other luteovirus for which there is data available. RPVa and RPVu were very similar, especially their coat proteins which had 97% identity at the amino acid level. The coat protein of GPV had 76% and 78% amino acid identity with RPVa and RPVu respectively. The data suggest that RPVu and RPVa are correctly named as strains of the same serotype and that GPV is sufficiently different from either RPV strain to be considered a distinct BYDV type. The coat protein and movement protein genes of GPV are very dissimilar to SGV. The polymerase sequences of RPVu, RPVa and GPV show close affinities with those of the sobemo-like luteoviruses and little similarity with those of the carmo-like luteoviruses. The sequences of the coat proteins, movement proteins and the polymerase segments of BYDV serotypes, other than RPV and GPV, form a cluster that is separate from their counterpart sequences from dicot-infecting luteoviruses. The RPV and GPV isolates consistently fall within a dicot-infecting cluster. This suggests that RPV and GPV evolved from within this group of viruses. Since these other viruses all infect dicots it seems likely that their common ancestor infected a dicot and that RPV and GPV evolved from a virus that switched hosts from a dicot to a monocot.

Proceedings of the 6th International Conference on Communities and Technologies

The Communities and Technologies 2013 conference received 46 submissions for full papers and 12 submissions for research in progress papers. From these submissions, 17 papers were selected to appear at the conference (29%). All submitted papers were subjected to double blind peer review by an independent international program committee of 51 experts.

To be continued... fan fiction and the constructing of identity

This chapter contributes to the existing body of knowledge on fan fiction by reporting the findings from a quantitative and qualitative study on fan fiction in a Swedish context. The authors contextualize the fan fiction phenomenon as a part of a larger transformation of the media sphere and the society in general where media consumers’ role as collaborative cultural producers grows ever stronger. They explore what kind of stories inspire the writers and conclude that as in many other parts of the entertainment industry, fan fiction is dominated by a small number of international media brands. The authors show how fan fiction can play an important role in the development of adolescents’ literacies and identities and how their pastime works as a vehicle for personal growth.

Literacies on the Web : Co-Production of Literary Texts on Fan Fiction Sites

In this chapter the authors discuss and informal learning settings such as fan fiction sites and their relations to teaching and learning within formal learning settings. Young people today spend a lot of time with social media built on user generated content. These media are often characterized by participatory culture which offers a good environment for developing skills and identity work. In this chapter the authors problematize fan fiction sites as informal learning settings where the possibilities to learn are powerful and significant. They also discuss the learning processes connected to the development of literacies. Here the rhetoric principle of “imitatio” plays a vital part as well as the co-production of texts on the sites, strongly supported by the beta reader and the power of positive feedback. They also display that some fans, through the online publication of fan fiction, are able to develop their craft in a way which previously have been impossible.

Experimental evaluation of an autonomous surface vehicle for water quality and greenhouse gas emission monitoring

This paper describes the experimental evaluation of a novel Autonomous Surface Vehicle capable of navigating complex inland water reservoirs and measuring a range of water quality properties and greenhouse gas emissions. The 16 ft long solar powered catamaran is capable of collecting water column profiles whilst in motion. It is also directly integrated with a reservoir scale floating sensor network to allow remote mission uploads, data download and adaptive sampling strategies. This paper describes the onboard vehicle navigation and control algorithms as well as obstacle avoidance strategies. Experimental results are shown demonstrating its ability to maintain track and avoid obstacles on a variety of large-scale missions and under differing weather conditions, as well as its ability to continuously collect various water quality parameters complimenting traditional manual monitoring campaigns.

The role of laboratory exercises in modern power engineering education at the University of Queensland

The University of Queensland (UQ) has extensive laboratory facilities associated with each course in the undergraduate electrical engineering program. The laboratories include machines and drives, power systems simulation, power electronics and intelligent equipment diagnostics. A number of postgraduate coursework programs are available at UQ and the courses associated with these programs also use laboratories. The machine laboratory is currently being renovated with i-lab style web based experimental facilities, which could be remotely accessed. Senior level courses use independent projects using laboratory facilities and this is found to be very useful to improve students' learning skill. Laboratory experiments are always an integral part of a course. Most of the experiments are conducted in a group of 2-3 students and thesis projects in BE and major projects in ME are always individual works. Assessment is done in-class for the performance and also for the report and analysis.

Short-term changes in axial length during simulations of typical far, intermediate and near tasks

Purpose: To investigate the changes in axial length with the combined effect of accommodation and angle of gaze (convergence and downward gaze) over 5 minutes in groups of myopes and emmetropes. Methods: A total of 31 subjects (nine emmetropes, 10 low myopes, and 12 moderate to high myopes) aged from 18 to 31 years were recruited. To measure ocular biometrics in inferonasal gaze with accommodation, an optical biometer (Lenstar LS900) was inclined on a tilt and height adjustable stage, with the subject’s chinrest mounted on a rotary stage to induce various levels of convergence by rotation of the subject’s head in primary or downward gaze. Initially, the subjects performed a distance viewing task in primary gaze for 10 minutes to provide a ‘wash-out’ period for prior visual tasks, and then the subject’s axial length and ocular biometrics were measured in nine different combinations of gaze/accommodation over 5 minutes. These nine sessions for all gaze measurements (i.e. three levels of accommodation 9 three levels of convergence) were completed across 3 days of testing (one accommodation condition on each day).The nine combinations of gaze/accommodation were based on those required to view the centre, right and left edges of a distant TV at 6 m in primary gaze, an intermediate task (i.e. computer at 50 cm in 10° downward gaze) and a near task (i.e. reading A4 page at 20 cm in 20° downward gaze). Subjects were wearing a custom built three-axes head tracker throughout the experiment that monitored subjects’ relative head movements (roll, pitch and yaw) during measurements. Results: A significant increase in axial length occurred with the combined effect of accommodation, convergence and downward gaze (repeated measures ANOVA, p < 0.001), with the greatest axial elongation during the near task in downward gaze with convergence (i.e. downward 20°/inward 33°, with 5 D accommodation) (mean change 33 ± 13 lm, after 5 minutes task) followed by the intermediate task (i.e. downward 10°/inward 25°, with 2 D accommodation) (mean change 14 ± 11 lm, after 5 minutes task).Changes in axial length for the distance task (i.e. primary gaze/9° convergence, with 0.16 D accommodation) were not statistically significant (mean change 4 ± 8 lm, after 5 minutes task, p > 0.05). Moderate to high myopes had a greater change in the axial length (mean change 40 ± 11 lm after 5 minutes of near task) than that of emmetropes (mean change 29 ± 15 lm after 5 minutes of near task) and low myopes (mean change 29 ± 16 lm after 5 minutes of near task) associated with time (p = 0.02) and accommodation by time (p = 0.03). Conclusions: The combination of accommodation, convergence and downward angle has a significant short term effect on axial length over time. The near task in downward gaze with convergence caused a greater change in axial length than the intermediate and distant visual tasks. The greater axial elongation measured in the infero-nasal direction with accommodation is most likely associated with a combination of biomechanical factors such as, extraocular muscle forces and ciliary muscle contraction.

Progression of human breast cancer cells from hormone-dependent to hormone-independent growth both in vitro and in vivo

We have isolated a series of sublines of the hormone-dependent MCF-7 human breast cancer cell line after selection both in vivo and in vitro for growth in the presence of subphysiological concentrations of estrogens. These sublines represent a model system for study of the processes leading to hormonal autonomy. The cells form growing tumors in ovariectomized athymic nude mice in the absence of estrogen supplementation but retain some responsivity to estrogen as determined by stimulation of the rate of tumor growth in vivo and by induction of progesterone receptor. An ovarian-independent but hormone-responsive phenotype may occur early in the natural progression to hormone-independent and unresponsive growth in breast cancer. We observed no change in the affinity or decrease in the level of expression of estrogen receptors and progesterone receptors among the sublines and the parental cells. Epidermal growth factor receptors are not overexpressed in ovarian-independent cells. Thus, altered hormone receptor expression may be a late event in the acquisition of a hormone-independent and unresponsive phenotype. Sublines isolated by in vivo but not in vitro selection are more invasive than the parental cells both in vivo and across an artificial basement membrane in vitro. Thus, as yet unknown tumor-host interactions may be important in the development of an invasive phenotype. Furthermore, acquisition of the ovarian-independent and invasive phenotypes can occur independently.

Models of social media adoption in emergency management organisations

Recent natural disasters such as the Haitian earthquake 2011, the South East Queensland floods 2011, the Japanese earthquake and tsunami 2011 and Hurricane Sandy in the United States of America in 2012, have seen social media platforms changing the face of emergency management communications, not only in times of crisis and also during business-as-usual operations. With social media being such an important and powerful communication tool, especially for emergency management organisations, the question arises as to whether the use of social media in these organisations emerged by considered strategic design or more as a reactive response to a new and popular communication channel. This paper provides insight into how the social media function has been positioned, staffed and managed in organisations throughout the world, with a particular focus on how these factors influence the style of communication used on social media platforms. This study has identified that the social media function falls on a continuum between two polarised models, namely the authoritative one-way communication approach and the more interactive approach that seeks to network and engage with the community through multi-way communication. Factors such the size of the organisation; dedicated resourcing of the social media function; organisational culture and mission statement; the presence of a social media champion within the organisation; management style and knowledge about social media play a key role in determining where on the continuum organisations sit in relation to their social media capability. This review, together with a forthcoming survey of Australian emergency management organisations and local governments, will fill a gap in the current body of knowledge about the evolution, positioning and usage of social media in organisations working in the emergency management field in Australia. These findings will be fed back to Industry for potential inclusion in future strategies and practices.

Design guidelines for a mobile app for wellbeing of emerging adults

Mental health of young people may be improved through the use of mental health mobile applications,because young people engage with this technology freely. Mental health of young people is improved through the application of positive psychology, studies of which show that regular practice of one’s signature strength increases happiness and wellbeing, while decreasing depression. The issue is how to develop a mobile application intervention so that regular practice of one’s signature strength in novel ways occurs. This research project seeks to develop design guidelines discovered through the application of design thinking, actively working with emerging adults. In addition, this research is framed by the Design Science Research methodology to ensure that the resultant application is relevant and tested rigorously. This paper discusses the theory behind the application and discusses the research methods and research design, and will share the preliminary findings of the discovered design principles.