p53 and DNA damage checkpoint responses in the human prostate

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer mortality in men. In 2004, 5237 new cases were diagnosed and altogether 25 664 men suffered from prostate cancer in Finland (Suomen Syöpärekisteri). Although extensively investigated, we still have a very rudimentary understanding of the molecular mechanisms leading to the frequent transformation of the prostate epithelium. Prostate cancer is characterized by several unique features including the multifocal origin of tumors and extreme resistance to chemotherapy, and new treatment options are therefore urgently needed. The integrity of genomic DNA is constantly challenged by genotoxic insults. Cellular responses to DNA damage involve elegant checkpoint cascades enforcing cell cycle arrest, thus facilitating damage repair, apoptosis or cellular senescence. Cellular DNA damage triggers the activation of tumor suppressor protein p53 and Wee1 kinase which act as executors of the cellular checkpoint responses. These are essential for genomic integrity, and are activated in early stages of tumorigenesis in order to function as barriers against tumor formation. Our work establishes that the primary human prostatic epithelial cells and prostatic epithelium have unexpectedly indulgent checkpoint surveillance. This is evidenced by the absence of inhibitory Tyr15 phosphorylation on Cdk2, lack of p53 response, radioresistant DNA synthesis, lack of G1/S and G2/M phase arrest, and presence of persistent gammaH2AX damage foci. We ascribe the absence of inhibitory Tyr15 phosphorylation to low levels of Wee1A, a tyrosine kinase and negative regulator of cell cycle progression. Ectopic Wee1A kinase restored Cdk2-Tyr15 phosphorylation and efficiently rescued the ionizing radiation-induced checkpoints in the human prostatic epithelial cells. As variability in the DNA damage responses has been shown to underlie susceptibility to cancer, our results imply that a suboptimal checkpoint arrest may greatly increase the accumulation of genetic lesions in the prostate epithelia. We also show that small molecules can restore p53 function in prostatic epithelial cells and may serve as a paradigm for the development of future therapeutic agents for the treatment of prostate cancer We hypothesize that the prostate has evolved to activate the damage surveillance pathways and molecules involved in these pathways only to certain stresses in extreme circumstances. In doing so, this organ inadvertently made itself vulnerable to genotoxic stress, which may have implications in malignant transformation. Recognition of the limited activity of p53 and Wee1 in the prostate could drive mechanism-based discovery of preventative and therapeutic agents.

Monitoring darkling beetle populations for resistance to spinosad

Management of insecticide resistance.

Information theory and resistance fluctuations in one-dimensional disordered conductors

A novel method is proposed to treat the problem of the random resistance of a strictly one-dimensional conductor with static disorder. For the probability distribution of the transfer matrix R of the conductor we propose a distribution of maximum information entropy, constrained by the following physical requirements: (1) flux conservation, (2) time-reversal invariance, and (3) scaling with the length of the conductor of the two lowest cumulants of ω, where R=exp(iω→⋅Jbhat). The preliminary results discussed in the text are in qualitative agreement with those obtained by sophisticated microscopic theories.

Resistance to tomato yellow leafcurl virus in tomato

Resistance to tomato yellow leafcurl virus in tomato.

Impact of Energy Quantization on the Performance of Current-Biased SET Circuits

The current-biased single electron transistor (SET) (CBS) is an integral part of almost all hybrid CMOS SET circuits. In this paper, for the first time, the effects of energy quantization on the performance of CBS-based circuits are studied through analytical modeling and Monte Carlo simulations. It is demonstrated that energy quantization has no impact on the gain of the CBS characteristics, although it changes the output voltage levels and oscillation periodicity. The effects of energy quantization are further studied for two circuits: negative differential resistance (NDR) and neuron cell, which use the CBS. A new model for the conductance of NDR characteristics is also formulated that includes the energy quantization term.

CRC50151 Resistance Management

Develop nationally agreed, standard methods for insect sample collection, resistance testing, and data management as a basis for a statistically robust and informative national resistance monitoring program.

Pre-emptive Breeding for Russian Wheat Aphid Resistance

The aims of the project are to 1) identify closely linked molecular markers to resistance genes and validate them in Australian wheat and barley backgrounds, and 2) introgress RWA resistance into Australian wheat and barley backgrounds.

CRC50150 Targeting mechanisms of phosphine resistance in stored grain pests

The objectives of this projects are: 1)To ensure the identification of genomic DNA markers for phosphine resistance in Rhyzopertha dominica and Tribolium castaneum; 2) To determine gene function of identified phosphine resistance genes in Rhyzopertha dominica and Tribolium castaneum; and 3) Predict future problems by characterising international resistances using our genes as a starting point to determine strong resistance can get by determining similarities with Australia.

Australian Herbicide Resistance Initiative (phase 4)

A national focus on strategic and applied research to minimise herbicide resistance in Australian cropping.

Genomics of fumigant resistance in grain pests

Collaborative project with Indian partners to study the genetics of phosphine resistance in Indian strains of grain pests.

CRC50116 - Resistance Monitoring

National Monitoring for resistance to phosphine and grain protectants.

Understanding and management of resistance to Group M, L and I Herbicides

This project will develop better understanding of resistance to glyphosate, paraquat and Group I herbicides to better inform weed management. The project will develop a range of tools for farm advisors to improve their confidence in decision making with respect to reducing the risk of glyphosate, Group I and paraquat resistance. These will include risk assessments, case studies and scenario exploring tools. The project will discuss with commercial providers the potential for new herbicide registrations. The project will establish farm advisor learning groups to work on the application of the research in local areas where resistance is already a major problem and to improve adoption of research outcomes from this and other projects.

Risk assessment and preventive strategies for herbicide resistance in NR (phase III)

The threat and management of glyphosate# resistant weeds are major issues facing northern region growers. At present five weeds are confirmed glyphosate-resistant: barnyard grass, liverseed grass, windmill grass, annual ryegrass and flaxleaf fleabane. This project used 25 experiments to investigate the ecology of the grass weeds, plus new or improved chemical and non-chemical control tactics for them. The refined glyphosate resistance model developed in this project used the experiments' findings to predict the long-term impacts on evolution of resistance and on seed bank numbers of resistant weeds. These data led to revised management and resistance avoidance strategies, which were published in the Reporter newsletter, and via an on-line risk assessment tool. - See more at: http://finalreports.grdc.com.au/UQ00054#sthash.oTkCN4Sk.dpuf