Sir Peter MacCallum Department of Oncology - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 441
-
ItemThe transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2015-01-15)Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc- and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of self-renewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance.
-
ItemCDK4/6 inhibition: the late harvest cycle begins(IMPACT JOURNALS LLC, 2016-08-02)
-
ItemmTORC1 and CK2 coordinate ternary and eIF4F complex assembly(NATURE PUBLISHING GROUP, 2016-04)Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.
-
ItemPro-tumorigenic role of ERα in prostate cancer cells(IMPACT JOURNALS LLC, 2015-06)
-
ItemNo Preview AvailablePheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma(ENDOCRINE SOC, 2016-03)CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. OBJECTIVE: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. DESIGN: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. RESULTS: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. CONCLUSIONS: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.
-
ItemComparing women pharmacy consumers' experiences with weight loss treatment in Victoria and Nottingham: a cross-sectional study.(Springer Science and Business Media LLC, 2014-06-28)BACKGROUND: There has been a recent increase in weight management services available in pharmacies across Australia and England. The aim of this study was to determine the following between women in Victoria and Nottingham: similarities and differences of what weight management options are preferred by women pharmacy consumers; how they feel about pharmacists providing advice in this area; and what they desire in a weight management program. METHOD: Women pharmacy consumers were randomly approached by a researcher in community pharmacies in Victoria and Nottingham and asked to complete a questionnaire regarding their own weight management experiences. The questionnaire was self-completed or researcher-administered and was comprised of four main sections that focused on the participant's general health, previous weight loss experiences, their ideal weight management program and their demographics. Data was entered in SPSS 19 and logistic regression was used to identify any differences in weight loss experiences between women. RESULTS: The participant rates were high: 86% (n = 395/460) in Victoria and 98% in Nottingham (n = 215/220). Overall, women in Victoria and Nottingham were similar with comparable demographics. Approximately 50% (250/507) of women were in the overweight or obese body mass index category, with over 70% (n = 436/610) of women having attempted to lose weight in the past. The majority of women (n = 334/436) felt comfortable receiving advice from pharmacists. In the logistic regression analysis women in Nottingham were found to be significantly less likely to have utilised a pharmacy weight management program in the last five years (OR: 0.23 CI: 0.08, 0.63) and were significantly less likely to want an ideal weight management program located in a pharmacy (OR: 0.49 CI: 0.30, 0.82) compared to women in Victoria. No significant associations between location and feeling comfortable with a pharmacist advising on weight loss or wanting a pharmacist in an ideal weight management program were seen. CONCLUSION: Results from this study have provided information on possible ideal pharmacy weight management programs in both Victoria and Nottingham. Although differences were seen between the two populations, similarities between ideal weight management programs and comfort level with pharmacist interaction were noted.
-
ItemProtocol for ACCESS: a qualitative study exploring barriers and facilitators to accessing the emergency contraceptive pill from community pharmacies in Australia(BMJ PUBLISHING GROUP, 2015)INTRODUCTION: The rate of unplanned pregnancy in Australia remains high, which has contributed to Australia having one of the highest abortion rates of developed countries with an estimated 1 in 5 women having an abortion. The emergency contraceptive pill (ECP) offers a safe way of preventing unintended pregnancy after unprotected sex has occurred. While the ECP has been available over-the-counter in Australian pharmacies for over a decade, its use has not significantly increased. This paper presents a protocol for a qualitative study that aims to identify the barriers and facilitators to accessing the ECP from community pharmacies in Australia. METHODS AND ANALYSIS: Data will be collected through one-on-one interviews that are semistructured and in-depth. Partnerships have been established with 2 pharmacy groups and 2 women's health organisations to aid with the recruitment of women and pharmacists for data collection purposes. Interview questions explore domains from the Theoretical Domains Framework in order to assess the factors aiding and/or hindering access to ECP from community pharmacies. Data collected will be analysed using deductive content analysis. The expected benefits of this study are that it will help develop evidence-based workforce interventions to strengthen the capacity and performance of community pharmacists as key ECP providers. ETHICS AND DISSEMINATION: The findings will be disseminated to the research team and study partners, who will brainstorm ideas for interventions that would address barriers and facilitators to access identified from the interviews. Dissemination will also occur through presentations and peer-reviewed publications and the study participants will receive an executive summary of the findings. The study has been evaluated and approved by the Monash Human Research Ethics Committee.
-
ItemOutcomes of patients with non-melanoma solid tumours receiving self-funded pembrolizumab at Chris O'Brien Lifehouse.(Wiley, 2016-12)BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown. AIM: To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.
-
ItemIntense focal pituitary FDG uptake due to intravascular large B-cell lymphoma in pyrexia of unknown origin(WILEY-BLACKWELL, 2016-11)
-
Item