A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

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.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer : report of a phase I/II dose-escalating study

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis. (C) 2000 Elsevier Science Ltd.

National survey of viruses in pastures of subterranean clover. I. Incidence of four viruses assessed by ELISA

A nationwide survey was made of the time-course incidence of alfalfa mosaic virus (AMV), clover yellow vein virus (CYVV), subterranean clover mottle virus (SCMoV) and subterranean clover red leaf virus (SCRLV) in improved pastures in southern regions of Australia. Averaged over all states, the highest mean incidence recorded for samples infected with individual viruses in either winter or spring was 9.4% for AMV, 5.7% for CYVV, 10.9% for SCMoV and 7.5% for SCRLV. For AMV and SCRLV, there was an increasing trend from spring 1984 to spring 1986. A similar increasing trend for SCMoV was more evident in winter than in spring. For CYVV, no time-course pattern was evident. Results support the proposition that viruses contribute significantly to "clover-decline', a well-known problem in pastures of Trifolium subterraneum. -from Authors

'I wouldn't say that' : finding a young adult, female voice in a Queensland mining town

This is a practice-led project consisting of a Young Adult novel, Open Cut, and an exegesis, 'I Wouldn't Say That': Finding a Young Adult, Female Voice in a Queensland Mining Town. The thesis investigates the use of first person narration in order to create an immediate engaging, realist Young Adult Fiction. The research design is bound by a feminist interpretative paradigm. The methodology employed is practice-led, auto-ethnography, and participant observation. Particular characteristics of first person narration used in Australian Young Adult Fiction are identified in an analysis of Dust, by Christine Bongers, and Jasper Jones, by Craig Silvey. The exegesis also contains a reflection on the researcher's creative work, and the process used to draft, edit, plot and construct the novel. The research contributes to knowledge in the field of Young Adult Literature because it offers a graphic portrayal of an Australian mining town that has not been heard before.

"I can't believe I just said that": Using guided reflections with non-Indigenous pre-service teachers in Australia

This paper explores the use of guided narrative reflection as a strategy used with high-achieving non-Indigenous pre-service teachers in Australia on teaching practicum. We suggest that reflections (and subsequent dialogue) can provide opportunities for non-Indigenous preservice teachers to re-think their beliefs and actions in ways that may intervene in the teaching that often causes educational disadvantage for Aboriginal and Torres Strait Islander students.

I still dream of my grandfather's red roses

"I still dream of my grandfather's red roses" is an online audio documentary. Asking people from her community to make a statement beginning with the words "I dream of", Australian documentarist Phoebe Hart curates these fragments and creatively envisages the literal and figurative world of dreams, arresting our collective hopes, desires and fears.

Role of Human Topoisomerase I in DNA Repair and Apoptosis

Human topoisomerase I (htopoI) is an enzyme that up to now was believed to function mainly in the removal of torsional stress generated during transcription and replication. In 1998, it was found that htopoI might play another important role in the cellular response to DNA damage -- the so-called htopoI damage response. Since this initial discovery, many studies have suggested that the htopoI damage response is involved in DNA repair as well as in apoptosis. Here we discuss the earliest as well as the latest results in this field. Combining all of the published and as yet unpublished results, we suggest and discuss a model of how htopoI may function during DNA repair and apoptosis. Furthermore, numerous results show that the htopoI damage response is not a spontaneous event, but is strictly regulated by cellular signalling pathways. We discuss which pathways may be involved and how the htopoI damage response is activated. Although the htopoI damage response was discovered several years ago, research in this area is just beginning. The future will surely bring more clarity regarding the precise mechanism behind the involvement of htopoI in DNA repair and apoptosis, as well as its implications for a broader understanding of how the human organism ensures genomic stability.

Improving short utterance i-vector speaker verification using utterance variance modelling and compensation techniques

This paper proposes techniques to improve the performance of i-vector based speaker verification systems when only short utterances are available. Short-length utterance i-vectors vary with speaker, session variations, and the phonetic content of the utterance. Well established methods such as linear discriminant analysis (LDA), source-normalized LDA (SN-LDA) and within-class covariance normalisation (WCCN) exist for compensating the session variation but we have identified the variability introduced by phonetic content due to utterance variation as an additional source of degradation when short-duration utterances are used. To compensate for utterance variations in short i-vector speaker verification systems using cosine similarity scoring (CSS), we have introduced a short utterance variance normalization (SUVN) technique and a short utterance variance (SUV) modelling approach at the i-vector feature level. A combination of SUVN with LDA and SN-LDA is proposed to compensate the session and utterance variations and is shown to provide improvement in performance over the traditional approach of using LDA and/or SN-LDA followed by WCCN. An alternative approach is also introduced using probabilistic linear discriminant analysis (PLDA) approach to directly model the SUV. The combination of SUVN, LDA and SN-LDA followed by SUV PLDA modelling provides an improvement over the baseline PLDA approach. We also show that for this combination of techniques, the utterance variation information needs to be artificially added to full-length i-vectors for PLDA modelling.

Cellular stress triggers the human topoisomerase I damage response independently of DNA damage in a p53 controlled manner

The 'human topoisomerase I (htopoI) damage response' was reported to be triggered by various kinds of DNA lesions. Also, a high and persistent level of htopoI cleavage complexes correlated with apoptosis. In the present study, we demonstrate that DNA damage-independent induction of cell death using colcemid and tumor necrosis factor is also accompanied by a strong htopoI response that correlates with the onset of apoptotic hallmarks. Consequently, these results suggest that htopoI cleavage complex formation may be caused by signaling pathways independent of the kind of cellular stress. Thus, protein interactions or signaling cascades induced by DNA damage or cellular stress might lead to the formation of stabilized cleavage complexes rather than the DNA lesion itself. Finally, we show that p53 not only plays a key role in the regulation of the htopoI response to UV-C irradiation but also to treatment with colcemid.

Higher-order non-linear analysis of steel structures. Part I : elastic second-order formulation

This paper presents a higher-order beam-column formulation that can capture the geometrically non-linear behaviour of steel framed structures which contain a multiplicity of slender members. Despite advances in computational frame software, analyses of large frames can still be problematic from a numerical standpoint and so the intent of the paper is to fulfil a need for versatile, reliable and efficient non-linear analysis of general steel framed structures with very many members. Following a comprehensive review of numerical frame analysis techniques, a fourth-order element is derived and implemented in an updated Lagrangian formulation, and it is able to predict flexural buckling, snap-through buckling and large displacement post-buckling behaviour of typical structures whose responses have been reported by independent researchers. The solutions are shown to be efficacious in terms of a balance of accuracy and computational expediency. The higher-order element forms a basis for augmenting the geometrically non-linear approach with material non-linearity through the refined plastic hinge methodology described in the companion paper.

The human topoisomerase I damage response plays a role in apoptosis

Previous studies have shown that human topoisomerase I cleavage complexes form as a response to various DNA damages in vivo, the so called human topoisomerase I “damage response”. It was suggested that this damage response may play a role in DNA repair as well as in apoptosis, but only very few investigations have been done and the significance of the damage response still remains unclear. Here we demonstrate that human topoisomerase I cleavage complexes induced by high doses of UV irradiation are highly stable for up to 48 h. Furthermore, we show that human topoisomerase I cleavage complexes correlate with apoptosis. However, at low UV doses the cleavage complex level was very low and the complexes were repaired. Surprisingly, we found that high levels of stable cleavage complexes were not only found in UV-irradiated cells but also in untreated cells that underwent apoptosis. A possible role of human topoisomerase I in apoptosis is discussed.

Fasting increases serum bilirubin levels in clinically normal, healthy males but not females : a retrospective study from phase I clinical trial participants

Aim: To examine if fasting affects serum bilirubin levels in clinical healthy males and females. Methods: We utilised retrospective data from phase 1 clinical trials where blood was collected in either a fed or fasting state at screening and pre-dosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n = 105) or females (n = 30) aged 18 to 48 inclusive who participated in a phase 1 clinical trial in 2012 or 2013. Results: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared to non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.