Intermittent Fugu parathyroid hormone 1 (1–34) is an anabolic bone agent in young male rats and osteopenic ovariectomized rats

Human parathyroid hormone (hPTH) is currently the only treatment for osteoporosis that forms new bone. Previously we described a fish equivalent, Fugu parathyroid hormone 1 (fPth1) which has hPTH-like biological activity in vitro despite fPth1(1–34) sharing only 53% identity with hPTH(1–34). Here we demonstrate the in vivo actions of fPth1(1–34) on bone. In study 1, young male rats were injected intermittently for 30 days with fPth1 [30 μg–1000 μg/kg body weight (b.w.), (30fPth1–1000fPth1)] or hPTH [30 μg–100 μg/kg b.w. (30hPTH–100hPTH)]. In proximal tibiae at low doses, the fPth1 was positively correlated with trabecular bone volume/total volume (TbBV/TV) while hPTH increased TbBV/TV, trabecular thickness (TbTh) and trabecular number (TbN). 500fPth1 and 1000fPth1 increased TbBV/TV, TbTh, TbN, mineral apposition rate (MAR) and bone formation rate/bone surface (BFR/BS) with a concomitant decrease in osteoclast surface and number. In study 2 ovariectomized (OVX), osteopenic rats and sham operated (SHAM) rats were injected intermittently with 500 μg/kg b.w. of fPth1 (500fPth1) for 11 weeks. 500fPth1 treatment resulted in increased TbBV/TV (151%) and TbTh (96%) in the proximal tibiae due to increased bone formation as assessed by BFR/BS (490%) and MAR (131%). The effect was restoration of TbBV/TV to SHAM levels without any effect on bone resorption. 500fPth1 also increased TbBV/TV and TbTh in the vertebrae (L6) and cortical thickness in the mid-femora increasing bone strength at these sites. fPth1 was similarly effective in SHAM rats. Notwithstanding the low amino acid sequence homology with hPTH (1–34), we have clearly established the efficacy of fPth1 (1–34) as an anabolic bone agent.

A visual profile of Queensland indigenous and non-indigenous school children, and the association between vision and reading

This research investigated the prevalence of vision disorders in Queensland Indigenous primary school children, creating the first comprehensive visual profile of Indigenous children. Findings showed reduced convergence ability and reduced visual information processing skills were more common in Indigenous compared to non-Indigenous children. Reduced visual information processing skills were also associated with reduced reading outcomes in both groups of children. As early detection of visual disorders is important, the research also reviewed the delivery of screening programs across Queensland and proposed a model for improved coordination and service delivery of vision screening to Queensland school children.

Exercise alters the profile of phospholipid molecular species in rat skeletal muscle

We have determined the effect of two exercise-training intensities on the phospholipid profile of both glycolytic and oxidative muscle fibers of female Sprague-Dawley rats using electrospray-ionization mass spectrometry. Animals were randomly divided into three training groups: control, which performed no exercise training; low-intensity (8 m/min) treadmill running; or high-intensity (28 m/min) treadmill running. All exercise-trained rats ran 1,000 m/session for 4 days/wk for 4 wk and were killed 48 h after the last training bout. Exercise training was found to produce no novel phospholipid species but was associated with significant alterations in the relative abundance of a number of phospholipid molecular species. These changes were more prominent in glycolytic (white vastus lateralis) than in oxidative (red vastus lateralis) muscle fibers. The largest observed change was a decrease of ∼20% in the abundance of 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine [PE(18:0/22:6); P < 0.001] ions in both the low- and high-intensity training regimes in glycolytic fibers. Increases in the abundance of 1-oleoyl-2-linoleoyl phopshatidic acid [PA(18:1/18:2); P < 0.001] and 1-alkenylpalmitoyl-2-linoleoyl phosphatidylethanolamine [plasmenyl PE (16:0/18:2); P < 0.005] ions were also observed for both training regimes in glycolytic fibers. We conclude that exercise training results in a remodeling of phospholipids in rat skeletal muscle. Even though little is known about the physiological or pathophysiological role of specific phospholipid molecular species in skeletal muscle, it is likely that this remodeling will have an impact on a range of cellular functions.

Radiographic imaging for traumatic ankle injuries : a demand profile and investigation of radiological reporting timeframes from an Australian tertiary facility

Background Radiographic examinations of the ankle are important in the clinical management of ankle injuries in hospital emergency departments. National (Australian) Emergency Access Targets (NEAT) stipulate that 90 percent of presentations should leave the emergency department within 4 hours. For a radiological report to have clinical usefulness and relevance to clinical teams treating patients with ankle injuries in emergency departments, the report would need to be prepared and available to the clinical team within the NEAT 4 hour timeframe; before the patient has left the emergency department. However, little is known about the demand profile of ankle injuries requiring radiographic examination or time until radiological reports are available for this clinical group in Australian public hospital emergency settings. Methods This study utilised a prospective cohort of consecutive cases of ankle examinations from patients (n=437) with suspected traumatic ankle injuries presenting to the emergency department of a tertiary hospital facility. Time stamps from the hospital Picture Archiving and Communication System were used to record the timing of three processing milestones for each patient's radiographic examination; the time of image acquisition, time of a provisional radiological report being made available for viewing by referring clinical teams, and time of final verification of radiological report. Results Radiological reports and all three time stamps were available for 431 (98.6%) cases and were included in analysis. The total time between image acquisition and final radiological report verification exceeded 4?hours for 404 (92.5%) cases. The peak demand for radiographic examination of ankles was on weekend days, and in the afternoon and evening. The majority of examinations were provisionally reported and verified during weekday daytime shift hours. Conclusions Provisional or final radiological reports were frequently not available within 4 hours of image acquisition among this sample. Effective and cost-efficient strategies to improve the support provided to referring clinical teams from medical imaging departments may enhance emergency care interventions for people presenting to emergency departments with ankle injuries; particularly those with imaging findings that may be challenging for junior clinical staff to interpret without a definitive radiological report.

Hormone resistance, invasiveness, and metastatic potential in breast cancer

Critical phenotypic changes that occur during the progression of breast cancer include the loss of hormone-dependence, acquired resistance to systemic therapies, and increased metastatic potential. We have isolated a series of MCF-7 human breast cancer variants which exhibit hormone-independent growth, antiestrogen resistance, and increased metastatic potential. Analysis of the phenotypes of these variants strongly suggests that changes in the expression of specific genes may be critical to the generation of phenotypic diversity in the process of malignant progression in breast cancer. Epigenetic changes may contribute significantly to the generation of these phenotypic changes observed during breast cancer progression. Many of the characteristics of the progressed phenotypes appear to have arisen in response to appropriate selective pressures (growth in ovariectomized nude mice; growth in the presence of antiestrogens). These observations are consistent with the concept of clonal selection and expansion in the process of malignant progression.

The invasive and metastatic properties of hormone-independent but hormone-responsive variants of MCF-7 human breast cancer cells

We have previously isolated a series of MCF-7 human breast cancer cell variants which no longer require estrogen-supplementation for tumor growth in nude mice (Clarke et al. Proc Natl Acad Sci USA 86: 3649-3653, 1989). We now report that these hormone-independent and hormone-responsive variants (MIII, MCF7/LCC1) can invade locally from solid mammary fat pad tumors, and produce primary extensions on the surface of intraperitoneal structures including liver, pancreas, and diaphragm. Both lymphatic and hematogenous dissemination are observed, resulting in the establishing of pulmonary, bone, and renal metastases. The pattern of metastasis by MIII and MCF7/LCC1 cells closely resembles that frequently observed in breast cancer patients, and provides the first evidence of metastasis from MCF-7 cells growing in vivo without supplementary estrogen. The interexperimental incidence of metastases, and the time from cell inoculation to the appearance of metastatic disease are variable. The increased metastatic potential is not associated with an increase in either the level of laminin attachment, laminin receptor mRNA expression, or secreted type IV collagenolytic activity. We also did not detect a significant decrease in the steady-state mRNA levels of the metastasis inhibitor nm23 gene. However, when growing without estrogen in vitro, MCF7/LCC1 cells produce elevated levels of the estrogen-inducible cathepsin D enzyme.

Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile

Epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) have been associated with resistance to chemotherapy. Eighty percent of ovarian cancer patients initially respond to platinum-based combination therapy but most return with recurrence and ultimate demise. To better understand such chemoresistance we have assessed the potential role of EMT in tumor cells collected from advanced-stage ovarian cancer patients and the ovarian cancer cell line OVCA 433 in response to cisplatin in vitro. We demonstrate that cisplatin-induced transition from epithelial to mesenchymal morphology in residual cancer cells correlated with reduced E-cadherin, and increased N-cadherin and vimentin expression. The mRNA expression of Snail, Slug, Twist, and MMP-2 were significantly enhanced in response to cisplatin and correlated with increased migration. This coincided with increased cell surface expression of CSC-like markers such as CD44, α2 integrin subunit, CD117, CD133, EpCAM, and the expression of stem cell factors Nanog and Oct-4. EMT and CSC-like changes in response to cisplatin correlated with enhanced activation of extracellular signal-regulated kinase (ERK)1/2. The selective MEK inhibitor U0126 inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and CSC markers. In vivo xenotransplantation of cisplatin-treated OVCA 433 cells in zebrafish embryos demonstrated significantly enhanced migration of cells compared to control untreated cells. U0126 inhibited cisplatin-induced migration of cells in vivo, suggesting that ERK2 signaling is critical to cisplatin-induced EMT and CSC phenotypes, and that targeting ERK2 in the presence of cisplatin may reduce the burden of residual tumor, the ultimate cause of recurrence in ovarian cancer patients.

The biology of breast tumor progression : acquisition of hormone independence and resistance to cytotoxic drugs

Many breast tumors appear to follow a predictable clinical pattern, being initially responsive to endocrine therapy and to cytotoxic chemotherapy but ultimately exhibiting a phenotype resistant to both modalities. Using the MCF-7 human breast cancer cell line as an example of an 'early' phenotype (estrogen and progesterone receptor positive, steroid responsive, low metastatic potential), we have isolated and characterized a series of hormone-independent but hormone-responsive variants (MIII and MCF7/LCC1). However, these variants remain responsive to both antiestrogens and cytotoxic drugs (methotrexate and colchicine). MIII and MCF7/LCCl cells appear to mimic some of the critical aspects of the early progression to a more aggressive phenotype. An examination of the phenotype of these cells suggests that some hormone-independent breast cancer cells are derived from hormone-dependent parental cells. The development of a hormone-independent phenotype can arise independently of acquisition of a cytotoxic drug resistant phenotype.

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.

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Characterising and predicting cyber attacks using the Cyber Attacker Model Profile (CAMP)

Purpose Ethnographic studies of cyber attacks typically aim to explain a particular profile of attackers in qualitative terms. The purpose of this paper is to formalise some of the approaches to build a Cyber Attacker Model Profile (CAMP) that can be used to characterise and predict cyber attacks. Design/methodology/approach The paper builds a model using social and economic independent or predictive variables from several eastern European countries and benchmarks indicators of cybercrime within the Australian financial services system. Findings The paper found a very strong link between perceived corruption and GDP in two distinct groups of countries – corruption in Russia was closely linked to the GDP of Belarus, Moldova and Russia, while corruption in Lithuania was linked to GDP in Estonia, Latvia, Lithuania and Ukraine. At the same time corruption in Russia and Ukraine were also closely linked. These results support previous research that indicates a strong link between been legitimate economy and the black economy in many countries of Eastern Europe and the Baltic states. The results of the regression analysis suggest that a highly skilled workforce which is mobile and working in an environment of high perceived corruption in the target countries is related to increases in cybercrime even within Australia. It is important to note that the data used for the dependent and independent variables were gathered over a seven year time period, which included large economic shocks such as the global financial crisis. Originality/value This is the first paper to use a modelling approach to directly show the relationship between various social, economic and demographic factors in the Baltic states and Eastern Europe, and the level of card skimming and card not present fraud in Australia.

Non-square-well potential profile and suppression of blinking in compositionally graded Cd1−xZnxSe/CdxZn1−xSe nanocrystals

Random blinking is a major problem on the way to successful applications of semiconducting nanocrystals in optoelectronics and photonics, which until recently had neither a practical solution nor a theoretical interpretation. An experimental breakthrough has recently been made by fabricating non-blinking Cd1-xZnxSe/ZnSe graded nanocrystals [Wang et al., Nature, 2009, 459, 686]. Here, we (1) report an unequivocal and detailed theoretical investigation to understand the properties (e.g., profile) of the potential-well and the distribution of Zn content with respect to the nanocrystal radius and (2) develop a strategy to find the relationship between the photoluminescence (PL) energy peaks and the potential-well due to Zn distribution in nanocrystals. It is demonstrated that the non-square-well potential can be varied in such a way that one can indeed control the PL intensity and the energy-level difference (PL energy peaks) accurately. This implies that one can either suppress the blinking altogether, or alternatively, manipulate the PL energy peaks and intensities systematically to achieve a controlled non-random intermittent luminescence. The approach developed here is based on the ionization energy approximation and as such is generic and can be applied to any non-free-electron nanocrystals.

A review of the profile of endothelin axis in cancer and its management

The endothelins and their associated receptors are important controllers of vascular growth, inflammation and vascular tone. In cancer, they have roles in the control of numerous factors in cancer development and progression, including angiogenesis, stromal reaction, epithelial mesenchymal transitions, apoptosis, invasion, metastases and drug resistance. Also, we consider current information on the role of this signalling system in cancer and examine the state of the current cell, animal and clinical trials utilizing endothelin targeted drugs for cancer management. Although targeting the endothelin axis in cell lines and xenografts show some promise in retarding cellular growth, results from limited clinical trials in prostatic cancer are less encouraging and did not offer significant survival benefit. The ability to target both cancer cells and vasculature via endothelin is an important consideration that necessitates the further refining of therapeutic strategies as we continue to explore the possibilities of the endothelin axis in cancer treatment.

Expression profile of endothelin 1 and its receptor endothelin receptor A in papillary thyroid carcinoma and their correlations with clinicopathologic characteristics

The endothelin axis is a group of signaling molecules and their receptors that have been implicated in vascularization of cancers, with their expression being observed to change in different cancer types. In this research, we examined the expression of endothelin 1 and endothelin receptor A at the protein and messenger RNA (mRNA) levels in 123 papillary thyroid carcinomas and 40 matched lymph nodes with metastatic papillary thyroid carcinomas. We found altered endothelin axis mRNA expression in several clinicopathologic parameters with increased endothelin 1 expression in thyroid papillary carcinoma showing stromal calcification, cancers in men, and primary cancers with lymph node metastases. Increased endothelin receptor A mRNA expression was noted in the larger cancers. There is a significant correlation between expression of endothelin receptor A and endothelin 1 in papillary thyroid carcinoma. Both endothelin receptor A and endothelin 1 mRNA expressions were significantly higher in metastatic carcinoma in the lymph node than in primary thyroid cancer. The metastatic carcinoma in the lymph node had increased expression compared with matched primary thyroid carcinoma. Expressions of endothelin 1 and endothelin receptor A were also documented as being high at the protein level. Our results indicate that in thyroid cancer, endothelin 1 and endothelin receptor A are associated with growth in advanced stages and lymph node metastases, likely through known angiogenic linkages. Targeting the endothelin axis may be useful in planning angiogenesis therapy for thyroid cancer.

Global start-ups profile : one size fits all?

Our research aims to answer the research questions “How do we commonly describe the global start-ups profile as evidenced in prior inductive research?” and “Does this global start-ups profile can effectively explain phenomena in Australian global start-up firms?” We systematically review 29 global start-ups (144 firms) qualitative articles to understand descriptive definitions of global-startup firms. We then triangulate this finding with an Australian high-tech firm. Our contribution is to form a descriptive profile of global start-up phenomenon and raise interesting issues that have potentially fruitful findings for both research and practice. This profile might well be just a deviant from the traditional model that describes how firms establish their footprints, first in their domestic markets followed by moves into cross-border activities. Regardless, government agencies, consultants, and entrepreneurs need to understand the phenomenon. Thus we anticipate that this phenomenon will continue to provide interesting issues for pursuit, both by researchers as well as the practitioner community.