Gene amplifications associated with the development of hormone- resistant prostate cancer

Purpose: Hormone resistance remains a significant clinical problem in prostate cancer with few therapeutic options. Research into mechanisms of hormone resistance is essential. Experimental Design: We analyzed 38 paired (prehormone/posthormone resistance) prostate cancer samples using the Vysis GenoSensor. Archival microdissected tumor DNA was extracted, amplified, labeled, and hybridized to Amplione I DNA microarrays containing 57 oncogenes. Results: Genetic instability increased during progression from hormone-sensitive to hormone-resistant cancer (P = 0.008). Amplification frequencies of 15 genes (TERC, MYBL3, HRAS, PI3KCA, JUNB, LAMC2, RAF1, MYC, GARP, SAS, FGFR1, PGY1, MYCL1, MYB, FGR) increased by greater than 10% during hormone escape. Receptor tyrosine kinases were amplified in 73% of cases; this was unrelated to development of hormone resistance. However, downstream receptor tyrosine kinase signaling pathways showed increased amplification rates in resistant tumors for the mitogen-activated protein kinase (FGR/Src-2, HRAS, and RAF1; P = 0.005) and phosphatidylinositol 3'-kinase pathways (FGR/ Src-2, PI3K, and Akt; P = 0.046). Transcription factors regulated by these pathways were also more frequently amplified after escape (MYC family: 21% before versus 63% after, P = 0.027; MYB family: 26 % before versus 53 % after, P = 0.18). Conclusions: Development of clinical hormone escape is linked to phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. These pathways may function independently of the androgen receptor or via androgen receptor activation by phosphorylation, providing novel therapeutic targets

An investigation into self-reported foot and lower limb problems associated with systemic lupus erythematosus (SLE): a research proposal

Systemic lupus erythematosus (SLE) can manifest in the lower limb with joint and muscle pains and in severe cases, disorganisation of the joints and tendon rupture. In the foot and lower limb, Raynaud’s phenomenon and other circulatory problems have been reported and may be associated with loss of sensation or altered pain perception. Associated with impaired peripheral neurovascular function are changes in tissue viability leading to either callus formation or thinning of the skin and ulceration. Many medications used to manage SLE can impact on the person’s resistance to infections and consequently fungal, bacterial or viral infections can spread rapidly and persist. Although there is some evidence for this range of problems occurring in the foot, it is not known how prevalent they are, what interaction there is between problems, and how these impact upon a person’s health related quality of life (HRQoL). Thus, the main aim of this study is to determine the self-reported foot and lower limb problems experienced by people with SLE. A secondary aim is to explore the impact that the identified foot and lower complications may have upon patients with SLE. It is anticipated that this research will highlight areas of potential health care need and thus can be used to inform recommendations about foot health care for this patient group and the focus of future research

A study of the effects of metallic pins on SAR using a Specific Anthropomorphic Mannequin (SAM) Head Phantom

This paper presents the effects of facial metallic pins on the Specific Absorption Rate (SAR) in the head, when radiated by a microwave source placed in front of the face. A Specific Anthropomorphic Mannequin (SAM) is adapted for use with a DASY4 and a digitised SAM head is modelled using inhouse Finite-Difference Time-Domain (FDTD) code, enabling comparisons between measurements and simulations. A continuous wave (CW) half-wave dipole is placed in front of the face, representing a communications enabled personal data assistant mobile communications equipment (PDAMCE). Parametric studies have shown that metallic pins that are roughly half a wavelength long placed along the eyebrow, increase the 1g and 10g SARs at 900MHz by around five fold. A greater than five fold increase is seen at 1800MHz. Measurements show very good agreement with simulations

Specific Absorption Rates in the human head due to circular metallic earrings at 1800MHz

This paper investigates Specific Absorption Rates (SAR) in the human head due to circular metallic earrings at 1800MHz. A Finite-Difference Time-Domain (FDTD) code was used to analyse different sizes and positions of circular earrings near a homogenous cubic phantom. Results showed good agreement with measurements using the flat section of the SAM twin phantom with the DASY4 measurement system. The excitation was a half wave dipole. Metallic loops with a circumference of approximately one wavelength and positioned 14mm away from the phantom increased the 10g SAR by 5 times. The FDTD code has also been used to analyse the effect of metallic earrings when ‘pierced’ through the ear of an anatomically realistic digital human head based on the Visible Human Project. The head is not symmetric and both ears were considered to allow comparison between different heads. The shape of the ear and the size of the earring were found to be very significant when earrings were hung from the human ear

The SAR effects of popular jewellery on the human head

This paper investigates the effects of metallic jewellery on the SAR in the human head. A CW dipole is placed in front of the head to represent a mobile enabled personal data assistant. The FDTD method has been used to simulate an eyebrow ring near a homogeneous SAM phantom at 1.8GHz. Measurements were made on the Loughborough SAM head with the DASY4 measurement system. Simulations were also made with eyebrow rings on the surface of the skin and pierced through the eyebrow of a heterogeneous anatomically realistic human head. Common sizes of eyebrow ring and eyebrow stud have been considered over the frequency range 0.6 to 4.6GHz. Jewellery which was small compared to a wavelength had little effect on the SAR in the head

Impact of high wind penetration on variability of unserved energy in power system adequacy

This paper presents results on variability of out-turn shortfalls about the expected value indices which are usually presented in resource adequacy studies, for a range of Loss of Load Expectation (LOLE) levels and installed wind capacities in a test system generally representative of future Great Britain system scenarios. While the details of results will clearly vary between systems, one very general conclusion is possible. In the results presented, for a given LOLE level, the probability of very severe out-turn in a future peak season is much greater at high installed wind capacity. Thus for this system, as the installed wind capacity increases, a constant level of LOLE cannot be taken as an indicator of an unchanging overall risk profile of the system. This further demonstrates that in any system, LOLE cannot be assumed to be a good summary statistic of risk profile as the installed variable generation (VG) capacity increases, and that it might be necessary to reconsider the near-universal use of expected value risk indices as the main headline indices in utility adequacy studies