Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. Conclusions This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies. Keywords: Ovarian carcinoma, Cancer stem cell, Metastasis, Ascites, Chemoresistance, Recurrence, JAK2/STAT3 pathway

Electron/ion energy loss to discharge walls revised : a case study in low-temperature, thermally nonequilibrium plasmas

Reliable calculations of the electron/ion energy losses in low-pressure thermally nonequilibrium low-temperature plasmas are indispensable for predictive modeling related to numerous applications of such discharges. The commonly used simplified approaches to calculation of electron/ion energy losses to the chamber walls use a number of simplifying assumptions that often do not account for the details of the prevailing electron energy distribution function (EEDF) and overestimate the contributions of the electron losses to the walls. By direct measurements of the EEDF and careful calculation of contributions of the plasma electrons in low-pressure inductively coupled plasmas, it is shown that the actual losses of kinetic energy of the electrons and ions strongly depend on the EEDF. It is revealed that the overestimates of the total electron/ion energy losses to the walls caused by improper assumptions about the prevailing EEDF and about the ability of the electrons to pass through the repulsive potential of the wall may lead to significant overestimates that are typically in the range between 9 and 32%. These results are particularly important for the development of power-saving strategies for operation of low-temperature, low-pressure gas discharges in diverse applications that require reasonably low power densities. © 2008 American Institute of Physics.

An application of the Driver Behaviour Questionnaire in a large Australian organisational fleeting setting : can it predict crashes and demerit point loss?

This study reports on the utilisation of the Manchester Driver Behaviour Questionnaire (DBQ) to examine the self-reported driving behaviours of a large sample of Australian fleet drivers (N = 3414). Surveys were completed by employees before they commenced a one day safety workshop intervention. Factor analysis techniques identified a three factor solution similar to previous research, which was comprised of: (a) errors, (b) highway-code violations and (c) aggressive driving violations. Two items traditionally related with highway-code violations were found to be associated with aggressive driving behaviours among the current sample. Multivariate analyses revealed that exposure to the road, errors and self-reported offences predicted crashes at work in the last 12 months, while gender, highway violations and crashes predicted offences incurred while at work. Importantly, those who received more fines at work were at an increased risk of crashing the work vehicle. However, overall, the DBQ demonstrated limited efficacy at predicting these two outcomes. This paper outlines the major findings of the study in regards to identifying and predicting aberrant driving behaviours and also highlights implications regarding the future utilisation of the DBQ within fleet settings.

Loss of neuronatin expression is associated with promoter hypermethylation in pituitary adenoma

The imprinted gene, neuronatin (NNAT), is one of the most abundant transcripts in the pituitary and is thought to be involved in the development and maturation of this gland. In a recent whole-genome approach, exploiting a pituitary tumour cell line, we identified hypermethylation associated loss of NNAT. In this report, we determined the expression pattern of NNAT in individual cell types of the normal gland and within each of the different pituitary adenoma subtypes. In addition, we determined associations between expression and CpG island methylation and used colony forming efficiency assays (CFE) to gain further insight into the tumour-suppressor function of this gene. Immunohistochemical (IHC) co-localization studies of normal pituitaries showed that each of the hormone secreting cells (GH, PRL, ACTH, FSH and TSH) expressed NNAT. However, 33 out of 47 adenomas comprising, 11 somatotrophinomas, 10 prolactinomas, 12 corticotrophinomas and 14 non-functioning tumours, irrespective of subtype failed to express either NNAT transcript or protein as determined by quantitative real-time RT-PCR and IHC respectively. In normal pituitaries and adenomas that expressed NNAT the promoter-associated CpG island showed characteristics of an imprinted gene where approximately 50% of molecules were densely methylated. However, in the majority of adenomas that showed loss or significantly reduced expression of NNAT, relative to normal pituitaries, the gene-associated CpG island showed significantly increased methylation. Induced expression of NNAT in transfected AtT-20 cells significantly reduced CFE. Collectively, these findings point to an important role for NNAT in the pituitary and perhaps tumour development in this gland.

Loss Control

A exhibition of sculptural assemblages that continue my exploration of self-portraiture and the sculptural object. The work specifically extends the formal vocabulary of my studio to incorporate smaller composite arrangements with an emphasis on the sculptural support. Small objects that are either modelled or cast from life are assembled into four tableaux that respond to the object-relations that arise through the production process. The resulting exhibiton thus acts a meditation on the ontology of art practice, conceived as a topology of objects.

Your Loss is Our Gain

2 x 2.5 metre text based wall painting with a hidden automatic air freshener timed to spray every 60 seconds. The work formed part of a group exhibition that dealt with Humour,Politics and Art. It was part of a series of ongoing works made under the pseudonym Eve Roleston. Roleston is part of a trio of pseudonyms I use, the others being Ernesto Love, and Ernest Olove, to explore the research potential of the fictocritical in a visual arts practice.This forms part of an ongoing body of practice-led research undertaken in my PhD dealing with reconfiguring the relationship between art and politics.

A loss of bioscience knowledge in nursing students

Background: Knowledge of the human biosciences is fundamental to the development of competent nurse practitioners (Smales, 2010) with the requisite knowledge and skills, necessary for high quality patient care and good patient outcomes (Logan and Angel, 2011). Many of these students study bioscience units which cover topics in anatomy, physiology, pathophysiology and microbiology. Studies of science recall in general and medical education, report up to 33% loss of knowledge in the first year which declines to 50% in the subsequent year (Custers, 2010). Objectives: The objectives were to test the recall of bioscience knowledge by nursing students and to ascertain their perceptions of the testing. Questions explored: What would the results be for multiple choice questions in fundamental microbiology and gastrointestinal anatomy and physiology (A&P) undertaken by nursing students 4, 9 and 16 months after their first bioscience exam on these topics? Would pre-warning the students of a microbiology quiz and not a gastrointestinal A&P quiz affect the findings? How would the students respond to the testing when surveyed? Recall results: The nursing students performed better in the final exam on gastrointestinal A&P than on fundamental microbiology. There was an approximate 20% loss in knowledge of gastrointestinal A&P after 4 months and this did not change significantly over the next 12 months. Although there was an improved performance in microbiology quizzes after 4 months, there was no significant difference in results over the next 12 months. Survey results: More than 50% of students thought the testing helped them focus for the lectures and made them aware they had some pre-knowledge of the lecture topics. Discussion: Although there was a loss of knowledge of gastrointestinal A&P, it appears that warning the students about the microbiology quiz may have helped their recall. The majority of students valued the testing as a useful learning exercise. References: Custers, E. J. F. M. (2010). Long-term retention of basic science knowledge: a review study. Advances in Health Science Education, 15, 109-128. Smales, K. (2010). Learning and applying biosciences to clinical practice in nursing. Nursing Standard, 24(33), 35-39. Logan, P.A., & Angel, L. (2011). Nursing as a scientific undertaking and the intersection with science in undergraduate studies: implications for nursing management. Journal of Nursing Management, 19(3), 407-417.

Estrogen deficiency-associated bone loss in the maxilla: A methodology to quantify the changes in the maxillary intra-radicular alveolar bone in an ovariectomized rat osteoporosis model

The effects of estrogen deficiency on bone characteristics are site-dependent, with the most commonly studied sites being appendicular long bones (proximal femur and tibia) and axial bones (vertebra). The effect on the maxillary and mandibular bones is still inconsistent and requires further investigation. This study was designed to evaluate bone quality in the posterior maxilla of ovariectomized rats in order to validate this site as an appropriate model to study the effect of osteoporotic changes. Methods: Forty-eight 3-month-old female Sprague-Dawley rats were randomly divided into two groups: an ovariectomized group (OVX, n=24) and Sham-operated group (SHAM, n=24). Six rats were randomly sacrificed from both groups at time points 8, 12, 16 and 20 weeks. The samples from tibia and maxilla were collected for Micro CT and histological analysis. For the maxilla, the volume of interest (VOI) area focused on the furcation areas of the first and second molar. Trabecular bone volume fraction (BV/TV, %), trabecular thickness (Tb.Th.), trabecular number (Tb.N.), trabecular separation (Tb.Sp.), and connectivity density (Conn.Dens) were analysed after Micro CT scanning. Results: At 8 weeks the indices BV/TV, Tb.Sp, Tb.N and Conn.Dens showed significant differences (P<0.05) between the OVX and SHAM groups in the tibia. Compared with the tibia, the maxilla developed osteoporosis at a later stage, with significant changes in maxillary bone density only occurring after 12 weeks. Compared with the SHAM group, both the first and second molars of the OVX group showed significantly decreased BV/TV values from 12 weeks, and these changes were sustained through 16 and 20 weeks. For Tb.Sp, there were significant increases in bone values for the OVX group compared with the SHAM group at 12, 16 and 20 weeks. Histological changes were highly consistent with Micro CT results. Conclusion: This study established a method to quantify the changes of intra-radicular alveolar bone in the posterior maxilla in an accepted rat osteoporosis model. The degree of the osteoporotic changes to trabecular bone architecture is site-dependent and at least 3 months are required for the osteoporotic effects to be apparent in the posterior maxilla following rat OVX.

Using the Driver Behaviour Questionnaire to predict crashes and demerit point loss : does it get better with larger sample sizes?

The Driver Behaviour Questionnaire (DBQ) continues to be the most widely utilised self-report scale globally to assess crash risk and aberrant driving behaviours among motorists. However, the scale also attracts criticism regarding its perceived limited ability to accurately identify those most at risk of crash involvement. This study reports on the utilisation of the DBQ to examine the self-reported driving behaviours (and crash outcomes) of drivers in three separate Australian fleet samples (N = 443, N = 3414, & N = 4792), and whether combining the samples increases the tool’s predictive ability. Either on-line or paper versions of the questionnaire were completed by fleet employees in three organisations. Factor analytic techniques identified either three or four factor solutions (in each of the separate studies) and the combined sample produced expected factors of: (a) errors, (b) highway-code violations and (c) aggressive driving violations. Highway code violations (and mean scores) were comparable across the studies. However, across the three samples, multivariate analyses revealed that exposure to the road was the best predictor of crash involvement at work, rather than DBQ constructs. Furthermore, combining the scores to produce a sample of 8649 drivers did not improve the predictive ability of the tool for identifying crashes (e.g., 0.4% correctly identified) or for demerit point loss (0.3%). The paper outlines the major findings of this comparative sample study in regards to utilising self-report measurement tools to identify “at risk” drivers as well as the application of such data to future research endeavours.

Consumer misbehavior: a concurrent look at the impact that the size of the victim and size of the loss have on opinions regarding the acceptance or unacceptance of 12 questionable consumer actions

This study examines the role that the size of a victimised organisation and the size of the victim’s loss have on attitudes regarding the acceptance or unacceptance of 12 questionable consumer actions. A sample of 815 American adults rated each scenario on a scale anchored by very acceptable and very unacceptable. It was shown that the size of the victimised organisation tends to influence consumers’ opinions with more disdain directed towards consumers who take advantage of smaller businesses. Similarly, the respondents tended to be more critical of these actions when the loss incurred by the victimised organisation was large. A 2x2 matrix concurrently delineated the nature of the extent to which opinions regarding the 12 actions differed depending upon the mediating variable under scrutiny.