Genome stability pathways in head and neck cancers

Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies

The radius and mass of the subgiant star bet Hyi from interferometry and asteroseismology

We have used the Sydney University Stellar Interferometer (SUSI) to measure the angular diameter of beta Hydri. This star is a nearby G2 subgiant whose mean density was recently measured with high precision using asteroseismology. We determine the radius and effective temperature of the star to be 1.814+/-0.017 R_sun (0.9%) and 5872+/-44 K (0.7%) respectively. By combining this value with the mean density, as estimated from asteroseismology, we make a direct estimate of the stellar mass. We find a value of 1.07+/-0.03 M_sun (2.8%), which agrees with published estimates based on fitting in the H-R diagram, but has much higher precision. These results place valuable constraints on theoretical models of beta Hyi and its oscillation frequencies.Comment: 3 figures, 3 tables, to appear in MNRAS Letter

Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy.

In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g x kg(-1) x wk(-1) or to a control group receiving epoetin alfa at an initial dose of 150 U x kg(-1) three times weekly. In part B, the cohorts were darbepoetin alfa 3.0 to 9.0 m.c.g x kg(-1) every 2 weeks or epoetin alfa, initial dose 40 000 U x wk(-1). Safety was assessed by adverse events, changes in blood pressure, and formation of antibodies to darbepoetin alfa. Efficacy was assessed by several haematologic endpoints, including change in haemoglobin from baseline. The adverse event profile of darbepoetin alfa was similar to that of epoetin alfa. No relationship between the rapidity of haemoglobin response and any adverse event was observed. No antibodies to darbepoetin alfa were detected. Higher doses of darbepoetin alfa increased the proportion of patients with a haemoglobin response and decreased the median time to response. The overall dose of darbepoetin alfa required to produce a mean increase in haemoglobin does not increase when the dosing interval is increased from 1 to 2 weeks. Therapy with darbepoetin alfa is safe and effective in producing a dose-related increase in haemoglobin levels in patients with cancer receiving chemotherapy

Characterization of hexabundles: Initial results

New multi-core imaging fibre bundles -- hexabundles -- being developed at the University of Sydney will provide simultaneous integral field spectroscopy for hundreds of celestial sources across a wide angular field. These are a natural progression from the use of single fibres in existing galaxy surveys. Hexabundles will allow us to address fundamental questions in astronomy without the biases introduced by a fixed entrance aperture. We have begun to consider instrument concepts that exploit hundreds of hexabundles over the widest possible field of view. To this end, we have compared the performance of a 61-core fully-fused hexabundle and 5 lightly-fused bundles with 7 cores each. All fibres in the bundles have 100 micron cores. In the fully-fused bundle, the cores are distorted from a circular shape in order to achieve a higher fill fraction. The lightly-fused bundles have circular cores and five different cladding thicknesses which affect the fill fraction. We compare the optical performance of all 6 bundles and find that the advantage of smaller interstitial holes (higher fill fraction) is outweighed by the increase in modal coupling, cross-talk and the poor optical performance caused by the deformation of the fibre cores. Uniformly high throughput and low cross-talk are essential for imaging faint astronomical targets with sufficient resolution to disentangle the dynamical structure. Devices already under development will have between 100 and 200 lightly-fused cores, although larger formats are feasible. The light-weight packaging of hexabundles is sufficiently flexible to allow existing robotic positioners to make use of them.Comment: Accepted for publication in MNRAS. See also a complimentary paper on the development of hexabundles - Bland-Hawthorn et al. 2011, Optics Express, vol. 19, p. 2649 (http://www.opticsinfobase.org/abstract.cfm?URI=oe-19-3-2649

Imaging Modalities for Cervical Spondylotic Stenosis and Myelopathy

Cervical spondylosis is a spectrum of pathology presenting as neck pain, radiculopathy, and myelopathy or all in combination. Diagnostic imaging is essential to diagnosis and preoperative planning. We discuss the modalities of imaging in common practice. We examine the use of imaging to differentiate among central, subarticular, and lateral stenosis and in the assessment of myelopathy

Epigenetics Underpinning the Regulation of the CXC (ELR+) Chemokines in Non-Small Cell Lung Cancer

Background: Angiogenesis may play a role in the pathogenesis of Non-Small Cell Lung cancer (NSCLC). The CXC (ELR+) chemokine family are powerful promoters of the angiogenic response. Methods: The expression of the CXC (ELR+) family members (CXCL1-3/GROα-γ, CXCL8/IL-8, CXCR1/2) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of these chemokines was examined in normal bronchial epithelial and NSCLC cell lines. Results: Overall, expression of the chemokine ligands (CXCL1, 2, 8) and their receptors (CXCR1/2) were down regulated in tumour samples compared with normal, with the exception of CXCL3. CXCL8 and CXCR1/2 were found to be epigenetically regulated by histone post-translational modifications. Recombinant CXCL8 did not stimulate cell growth in either a normal bronchial epithelial or a squamous carcinoma cell line (SKMES-1). However, an increase was observed at 72 hours post treatment in an adenocarcinoma cell line. Conclusions: CXC (ELR+) chemokines are dysregulated in NSCLC. The balance of these chemokines may be critical in the tumour microenvironment and requires further elucidation. It remains to be seen if epigenetic targeting of these pathways is a viable therapeutic option in lung cancer treatment. © 2011 Baird et al

Operative Outcomes for Cervical Myelopathy and Radiculopathy

Cervical spondylotic myelopathy and radiculopathy are common disorders which can lead to significant clinical morbidity. Conservative management, such as physical therapy, cervical immobilisation, or anti-inflammatory medications, is the preferred and often only required intervention. Surgical intervention is reserved for those patients who have intractable pain or progressive neurological symptoms. The goals of surgical treatment are decompression of the spinal cord and nerve roots and deformity prevention by maintaining or supplementing spinal stability and alleviating pain. Numerous surgical techniques exist to alleviate symptoms, which are achieved through anterior, posterior, or circumferential approaches. Under most circumstances, one approach will produce optimal results. It is important that the surgical plan is tailored to address each individual's unique clinical circumstance. The objective of this paper is to analyse the major surgical treatment options for cervical myelopathy and radiculopathy focusing on outcomes and complications

Hypersonic Separated Flows About "Tick" Configurations With Sensitivity to Model Design

This paper presents computational results obtained by applying the direct simulation Monte Carlo (DSMC) method for hypersonic nonequilibrium flow about "tick-shaped" model configurations. These test models produces a complex flow where the nonequilibrium and rarefied aspects of the flow are initially enhanced as the flow passes over an expansion surface, and then the flow encounters a compression surface that can induce flow separation. The resulting flow is such that meaningful numerical simulations must have the capability to account for a significant range of rarefaction effects; hence the application of the DSMC method in the current study as the flow spans several flow regimes, including transitional, slip, and continuum. The current focus is to examine the sensitivity of both the model surface response (heating, friction and pressure) and flowfield structure to assumptions regarding surface boundary conditions and more extensively the impact of model design as influenced by leading edge configuration as well as the geometrical features of the expansion and compression surfaces. Numerical results indicate a strong sensitivity to both the extent of the leading edge sharpness and the magnitude of the leading edge bevel angle. Also, the length of the expansion surface for a fixed compression surface has a significant impact on the extent of separated flow

BCP crystals increase prostacyclin production and upregulate the prostacyclin receptor in OA synovial fibroblasts: potential effects on mPGES1 and MMP-13

SummaryObjectiveTo investigate the potential involvement of prostacyclin in basic calcium phosphate (BCP) crystal-induced responses in osteoarthritic synovial fibroblasts (OASF).MethodsOASF grown in culture were stimulated with BCP crystals. Prostacyclin production was measured by enzyme immunoassay. Expression of messenger RNA (mRNA) transcripts was assessed by real-time polymerase chain reaction (PCR). Expression of prostacyclin synthase (PGIS) and the prostacyclin (IP) receptor was measured. The effects of iloprost, a prostacyclin analogue, on expression of genes implicated in osteoarthritis such as microsomal prostaglandin E2 synthase 1 (mPGES1) and matrix metalloproteinases (MMPs) were also studied. FPT inhibitor II, a farnesyl transferase inhibitor, was used to antagonize iloprost-induced responses.ResultsBCP crystal stimulation led to a five-fold increase in prostacyclin production in OASF compared to untreated cells. This induction was attenuated by cyclooxygenase (COX)-2 and COX-1 inhibition at 4 and 32h, respectively. PGIS and IP receptor transcripts were constitutively expressed in OASF. BCP crystals upregulated IP receptor expression two-fold. While iloprost diminished BCP crystal-stimulated IP receptor upregulation, the inhibitory effect of iloprost was blocked by the farnesyl transferase inhibitor. In addition, iloprost upregulated mPGES1 and downregulated MMP-13 expression in BCP crystal-stimulated OASF, effects that were not influenced by the farnesyl transferase inhibitor.ConclusionsThese data showed for the first time that BCP crystals can increase prostacyclin production and upregulate expression of the IP receptor in OASF. The potential of prostacyclin to influence BCP crystal-stimulated responses was supported by the effects of iloprost on the expression of the IP receptor, mPGES1 and MMP-13. These data demonstrate the potential involvement of prostacyclin in BCP crystal-associated osteoarthritis (OA) and suggest that inhibition of PG synthesis with non-steroidal anti-inflammatory drugs may have both deleterious and beneficial effects in BCP crystal-associated OA

Operative Techniques for Cervical Radiculopathy and Myelopathy

Cervical spondylosis is a common problem encountered in modern orthopaedic practice. It is associated with significant patient morbidity related to the consequent radiculopathic and myelopathic symptoms. Operative intervention for this condition is generally indicated if conservative measures fail; however there are some circumstances in which urgent surgical intervention is necessary. Planning any surgical intervention must take into account a number of variables including, but not limited to, the nature, location and extent of the pathology, a history of previous operative interventions, and patient co-morbidities. There are many different surgical options and a multitude of different procedures have been described using both the anterior and posterior approaches to the cervical spine. The use of autograft to achieve cervical fusion is still the gold standard with allograft showing similar results; however fusion techniques are constantly evolving with novel synthetic bone graft substitutes now widely available