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Ghrelin is a peptide hormone which, when acylated, regulates appetite, energy balance and a range of other biological processes. Ghrelin predominately circulates in its unacylated form (unacylated ghrelin; UAG). UAG has a number of functions independent of acylated ghrelin, including modulation of metabolic parameters and cancer progression. UAG has also been postulated to antagonise some of the metabolic effects of acyl-ghrelin, including its effects on glucose and insulin regulation. In this study, Rag1-/- mice with high-fat diet-induced obesity and hyperinsulinaemia were subcutaneously implanted with PC3 prostate cancer xenografts to investigate the effect of UAG treatment on metabolic parameters and xenograft growth. Daily intraperitoneal injection of 100 μg/kg UAG had no effect on xenograft tumour growth in mice fed normal rodent chow or 23% high-fat diet. UAG significantly improved glucose tolerance in host Rag1-/- mice on a high-fat diet, but did not significantly improve other metabolic parameters. We propose that UAG is not likely to be an effective treatment for prostate cancer, with or without associated metabolic syndrome.

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. Here, the long-term effects of a 23% Western high-fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1 −/− ) suitable for engraftment with human-derived tissue xenografts, and the effect of diet-induced hyperinsulinaemia on human prostate cancer cell line xenograft growth, were investigated. Rag1 −/− and NOD/SCID HFD-fed mice demonstrated diet-induced impairments in glucose tolerance at 16 and 23 weeks post weaning. Rag1 −/− mice developed significantly higher fasting insulin levels (2.16 ± 1.01 ng/ml, P  = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, P  = 0.01) compared to low-fat chow-fed mice (0.71 ± 0.12 ng/ml and 2.91 ± 0.42 HOMA-IR). This was not observed in the NOD/SCID strain. Hepatic steatosis was more extensive in Rag1 −/− HFD-fed mice compared to NOD/SCID mice. Intramyocellular lipid storage was increased in Rag1 −/− HFD-fed mice, but not in NOD/SCID mice. In Rag1 −/− HFD-fed mice, LNCaP xenograft tumours grew more rapidly compared to low-fat chow-fed mice. This is the first characterisation of the metabolic effects of long-term Western HFD in two mouse strains suitable for xenograft studies. We conclude that Rag1 −/− mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia.

Whilst quantitative ultrasound can be reliably used to assess bone health in adults, the fixed location of the transducers in current devices may result in inaccurate and unreliable measurements in bone assessment in children due to the variation in foot size during growth. To improve positioning for paediatric assessment, Jaworski et al. (1995) created an anatomical method to identify the region of interest (ROI), however, there have been no medical imaging studies to confirm that the Jaworski method results in consistent placement of the transducer on the centre of the calcaneal body to avoid edge artefacts. In this study, computed tomography scans of the tarsus were collected from 498 individuals (258 females; 240 males) aged 2 to 20 years and used to create three novel anatomical methods to identify ROI on the calcaneus using palpable landmarks. In addition, the established Jaworski method was applied to the same scans and compared to our novel methods. The maximum ROI significantly increased with age with males having significantly greater diameters, supporting the recommendation that ½ inch diameter transducers should be used on individuals younger than 7 years of age. We identified that 79% of the ‘Jaworski points’ lied anterosuperior to the ROI centre point identified in this study, with 10% of the points lying outside the ROI. Of the three novel methods, only the calcaneal insertion method demonstrated small measurement variance between individuals of the same age in each sex and is therefore the preferred method for ultrasound clinical application.

•Standardized virtual protocols to conduct linear skeletal measurements are needed.•A standardized virtual protocol for linear skeletal measurements is introduced.•Semi-automated anthropometric measurements using CAD software have high reliability.•3D virtual protocols have broad application to forensic anthropology. This study introduces a standardized protocol for conducting linear measurements of postcranial skeletal elements using three-dimensional (3D) models constructed from post-mortem computed tomography (PMCT) scans. Using femoral DICOM datasets, reference planes were generated and plane-to-plane measurements were conducted on 3D surface rendered models. Bicondylar length, epicondylar breadth, anterior-posterior (AP) diameter, medial-lateral (ML) diameter and cortical area at the midshaft were measured by four observers to test the measurement error variance and observer agreement of the protocol (n=6). Intra-observer error resulted in a mean relative technical error of measurement (%TEM) of 0.11 and an intraclass correlation coefficient (ICC) of 0.999 (CI=0.998–1.000); inter-observer error resulted in a mean %TEM of 0.54 and ICC of 0.996 (CI=0.979–1.000) for bicondylar length. Epicondylar breadth, AP diameter, ML diameter and cortical area also yielded minimal error. Precision testing demonstrated that the approach is highly repeatable and is recommended for implementation in anthropological investigation and research. This study exploits the benefits of virtual anthropology, introducing an innovative, standardized alternative to dry bone osteometric measurements.

Despite the prominent use of the pubic symphysis for age estimation in forensic anthropology, little has been documented regarding the quantitative morphological and micro-architectural changes of this surface. Specifically, utilising post-mortem computed tomography data from a large, contemporary Australian adult population, this study aimed to evaluate sexual dimorphism in the morphology and bone composition of the symphyseal surface; and temporal characterisation of the pubic symphysis in individuals of advancing age. The sample consisted of multi-slice computed tomography (MSCT) scans of the pubic symphysis (slice thickness: 0.5mm, overlap: 0.1mm) of 200 individuals of Caucasian ancestry aged 15–70 years, obtained in 2011. Surface rendering reconstruction of the symphyseal surface was conducted in OsiriX® (v.4.1) and quantitative analyses in Rapidform XOS™ and Osteomeasure™. Morphometric variables including inter-pubic distance, surface area, circumference, maximum height and width of the symphyseal surface and micro-architectural assessment of cortical and trabecular bone compositions were quantified using novel automated engineering software capabilities. The major results of this study are correlated with the macroscopic ossification and degeneration pattern of the symphyseal surface, demonstrating significant age-related changes in the morphometric and bone tissue variables between 15 and 70 years. Regardless of sex, the overall dimensions of the symphyseal surface increased with age, coupled with a decrease in bone mass in the trabecular and cortical bone compartments. Significant differences between the ventral, dorsal and medial cortical surfaces were observed, which may be correlated to bone formation activity dependent on muscle activity and ligamentous attachments. Our study demonstrates significant sexual dimorphism at this site, with males exhibiting greater surface dimensions than females. These baseline results provide a detailed insight into the changes in the structure of the pubic symphysis with ageing and sexually dimorphic features associated with the cortical and trabecular bone profiles.

Despite the recognized flaws in applying traditional stature estimation equations such as those of Trotter and Gleser (1952) [5] to a contemporary population, there are currently no available alternatives for stature estimation in Australia that address these limitations. Post mortem computed tomography (PMCT) DICOM scans of the left and right femora were acquired from 76 Australian deceased individuals aged 17–76 years for metric analysis. Femoral bicondylar length, femoral epicondylar breadth and anterior–posterior (AP) diameter, medial-lateral (ML) diameter, circumference and cortical area at the femoral midshaft were measured on three-dimensional (3D) models to build statistical models for estimating stature. In addition, Australian individuals aged 16–63 years (n=111) were measured in standing and supine positions to aid in the adjustment of supine stature of deceased individuals utilized in this study to standing stature. The results of this preliminary evaluation strongly indicate that the optimal model for estimating stature includes bicondylar femoral length and epicondylar breadth, that the effect of sex as an independent variable is very low, and there is limited practical benefit in including age in the estimation of stature. Our study indicates that the Australian population sampled represents a small yet significant shift in stature from the original Trotter and Gleser sample. Additionally, in the case of fragmentary remains, it was found that epicondylar breadth and AP diameter had the highest probability of accurate stature estimation in the absence of bicondylar femoral length. As stature forms a significant component of a biological profile and therefore aids in the personal identification of human remains, it is important that forensic anthropologists utilize the most accurate methodologies available. Stature estimation of Australian individuals is therefore achieved with higher accuracy through utilizing the femoral equations proposed in this study.

Currently used xenograft models for prostate cancer bone metastasis lack the adequate tissue composition necessary to study the interactions between human prostate cancer cells and the human bone microenvironment. We introduce a tissue engineering approach to explore the interactions between human tumor cells and a humanized bone microenvironment. Scaffolds, seeded with human primary osteoblasts in conjunction with BMP7, were implanted into immunodeficient mice to form humanized tissue engineered bone constructs (hTEBCs) which consequently resulted in the generation of highly vascularized and viable humanized bone. At 12 weeks, PC3 and LNCaP cells were injected into the hTEBCs. Seven weeks later the mice were euthanized. Micro-CT, histology, TRAP, PTHrP and osteocalcin staining results reflected the different characteristics of the two cell lines regarding their phenotypic growth pattern within bone. Microvessel density, as assessed by vWF staining, showed that tumor vessel density was significantly higher in LNCaP injected hTEBC implants than in those injected with PC3 cells ( p  < 0.001). Interestingly, PC3 cells showed morphological features of epithelial and mesenchymal phenotypes suggesting a cellular plasticity within this microenvironment. Taken together, a highly reproducible humanized model was established which is successful in generating LNCaP and PC3 tumors within a complex humanized bone microenvironment. This model simulates the conditions seen clinically more closely than any other model described in the literature to date and hence represents a powerful experimental platform that can be used in future work to investigate specific biological questions relevant to bone metastasis.

Ghrelin is a peptide hormone which, when acylated, regulates appetite, energy balance and a range of other biological processes. Ghrelin predominately circulates in its unacylated form (unacylated ghrelin; UAG). UAG has a number of functions independent of acylated ghrelin, including modulation of metabolic parameters and cancer progression. UAG has also been postulated to antagonise some of the metabolic effects of acyl-ghrelin, including its effects on glucose and insulin regulation. In this study, Rag1-/- mice with high-fat diet-induced obesity and hyperinsulinaemia were subcutaneously implanted with PC3 prostate cancer xenografts to investigate the effect of UAG treatment on metabolic parameters and xenograft growth. Daily intraperitoneal injection of 100 g/kg UAG had no effect on xenograft tumour growth in mice fed normal rodent chow or 23% high-fat diet. UAG significantly improved glucose tolerance in host Rag1-/- mice on a high-fat diet, but did not significantly improve other metabolic parameters. We hypothesise that UAG is not likely to be an effective treatment for prostate cancer, with or without associated metabolic syndrome.