IGF2 increases de novo steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

Lignocellulosics as a renewable feedstock for chemical industry : chemical hydrolysis and pretreatment processes

Lignocellulosic materials including agricultural, municipal and forestry residues, and dedicated bioenergy crops offer significant potential as a renewable feedstock for the production of fuels and chemicals. These products can be chemically or functionally equivalent to existing products that are produced from fossil-based feedstocks. To unlock the potential of lignocellulosic materials, it is necessary to pretreat or fractionate the biomass to make it amenable to downstream processing. This chapter explores current and developing technologies for the pretreatment and fractionation of lignocellulosic biomass for the production of chemicals and fuels.

Triclosan and benzophenone-3 in Australian pooled infant urine

The period of developmental vulnerability begins at conception and extends through gestation, parturition, infanthood and adolescence. The World Health Organisation (WHO) acknowledges that children experience quantitatively and qualitatively different exposures to chemicals than adults, and that children may be more or less sensitive to a chemical than adults [1, 2]. For instance, because of mouthing behaviours, children have higher exposure to chemicals through non-dietary ingestion than adults [3, 4], and the possibility exists for different metabolism and/or toxicity between different groups due to the immaturity of defense mechanisms that are fully developed in adults [1]. Traditional toxicological studies are inappropriate for assessing the results of exposure at very low levels during critical periods of development. Biomonitoring data can be used to identify where policies should be directed in order to reduce exposure.

Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Long terminal repeats act as androgen-responsive enhancers for the PSA-Kallikrein locus

The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasize the importance of repetitive elements as functional regulatory units

A framework for automated identification of attack scenarios on IT infrastructures

Due to increased complexity, scale, and functionality of information and telecommunication (IT) infrastructures, every day new exploits and vulnerabilities are discovered. These vulnerabilities are most of the time used by ma¬licious people to penetrate these IT infrastructures for mainly disrupting business or stealing intellectual pro¬perties. Current incidents prove that it is not sufficient anymore to perform manual security tests of the IT infra¬structure based on sporadic security audits. Instead net¬works should be continuously tested against possible attacks. In this paper we present current results and challenges towards realizing automated and scalable solutions to identify possible attack scenarios in an IT in¬frastructure. Namely, we define an extensible frame¬work which uses public vulnerability databases to identify pro¬bable multi-step attacks in an IT infrastructure, and pro¬vide recommendations in the form of patching strategies, topology changes, and configuration updates.

Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia

Context: The benefits of high serum levels of 25-hydroxyvitamin D [25(OH)D] are unclear. Trials are needed to establish an appropriate evidence base. Objective: We plan to conduct a large-scale trial of vitamin D supplementation for the reduction of cancer incidence and overall mortality and report here the methods and results of a pilot trial established to inform its design. Design: Pilot D-Health was a randomized trial carried out in a general community setting with 12 months intervention and follow-up. Participants: Participants were 60- to 84-yr-old residents of one of the four eastern Australian states who did not have any vitamin D-related disorders and who were not taking more than 400 IU supplementary vitamin D per day. A total of 644 participants were randomized, and 615 completed the study (two persons withdrew because of nonserious adverse events). Interventions: The interventions were monthly doses of placebo or 30,000 or 60,000 IU vitamin D3. Main Outcomes: The main outcomes were the recruitment rate and changes in serum 25(OH)D. Results: Ten percent of those approached were recruited. At baseline, the mean 25(OH)D was 42 nmol/liter in all three study arms. The mean change in 25(OH)D in the placebo group was 0.12 nmol/liter, compared with changes of 22 and 36 nmol/liter in the 30,000- and 60,000-IU groups, respectively. Conclusions: The D-Health pilot has shown that a large trial is feasible in Australia and that a dose of 2000 IU/d will be needed to ensure that a large proportion of the population reaches the target serum 25(OH)D level. Copyright © 2012 by The Endocrine Society.

Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy

The assembly of retroviruses such as HIV-1 is driven by oligomerization of their major structural protein, Gag. Gag is a multidomain polyprotein including three conserved folded domains: MA (matrix), CA (capsid) and NC (nucleocapsid)(1). Assembly of an infectious virion proceeds in two stages(2). In the first stage, Gag oligomerization into a hexameric protein lattice leads to the formation of an incomplete, roughly spherical protein shell that buds through the plasma membrane of the infected cell to release an enveloped immature virus particle. In the second stage, cleavage of Gag by the viral protease leads to rearrangement of the particle interior, converting the non-infectious immature virus particle into a mature infectious virion. The immature Gag shell acts as the pivotal intermediate in assembly and is a potential target for anti-retroviral drugs both in inhibiting virus assembly and in disrupting virus maturation(3). However, detailed structural information on the immature Gag shell has not previously been available. For this reason it is unclear what protein conformations and interfaces mediate the interactions between domains and therefore the assembly of retrovirus particles, and what structural transitions are associated with retrovirus maturation. Here we solve the structure of the immature retroviral Gag shell from Mason-Pfizer monkey virus by combining cryo-electron microscopy and tomography. The 8-angstrom resolution structure permits the derivation of a pseudo-atomic model of CA in the immature retrovirus, which defines the protein interfaces mediating retrovirus assembly. We show that transition of an immature retrovirus into its mature infectious form involves marked rotations and translations of CA domains, that the roles of the amino-terminal and carboxy-terminal domains of CA in assembling the immature and mature hexameric lattices are exchanged, and that the CA interactions that stabilize the immature and mature viruses are almost completely distinct.

Temporal trend of organochlorine pesticides in Australia

Persistent, lipophilic organochlorine pesticides (OCPs) such as dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexanes (HCHs), dieldrin, chlordanes, hexachlorobenzene (HCB) and mirex are known to accumulate in human samples [1, 2]. Persistent OCPs are among the chemicals that are covered under the Stockholm Convention on persistent organic pollutants [3]. Exceptions to this include relatively less lipophillic compounds like HCH (KOW<10^5). In Australia, OCPs such as DDT and HCHs were introduced in the 1940s. This followed a period of widespread use until the 1970s when recognition of risks related to OCPs resulted in reduced use and their ultimate ban in the 1980s. Mirex, however, remained in very restricted use in Northern Australia for treatment of one species of termites (the Giant Termite (Mastotermes darwinensis)) but this use was phased out in 2007.

Using a pharmacokinetic model to interpret biomonitoring data of PBDEs in the Australian population

From human biomonitoring data that are increasingly collected in the United States, Australia, and in other countries from large-scale field studies, we obtain snap-shots of concentration levels of various persistent organic pollutants (POPs) within a cross section of the population at different times. Not only can we observe the trends within this population with time, but we can also gain information going beyond the obvious time trends. By combining the biomonitoring data with pharmacokinetic modeling, we can re-construct the time-variant exposure to individual POPs, determine their intrinsic elimination half-lives in the human body, and predict future levels of POPs in the population. Different approaches have been employed to extract information from human biomonitoring data. Pharmacokinetic (PK) models were combined with longitudinal data1, with single2 or multiple3 average concentrations of a cross-sectional data (CSD), or finally with multiple CSD with or without empirical exposure data4. In the latter study, for the first time, the authors based their modeling outputs on two sets of CSD and empirical exposure data, which made it possible that their model outputs were further constrained due to the extensive body of empirical measurements. Here we use a PK model to analyze recent levels of PBDE concentrations measured in the Australian population. In this study, we are able to base our model results on four sets5-7 of CSD; we focus on two PBDE congeners that have been shown3,5,8-9 to differ in intake rates and half-lives with BDE-47 being associated with high intake rates and a short half-life and BDE-153 with lower intake rates and a longer half-life. By fitting the model to PBDE levels measured in different age groups in different years, we determine the level of intake of BDE-47 and BDE-153, as well as the half-lives of these two chemicals in the Australian population.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

Characterization and catalytic performance of Fe3Ni8/palygorskite for catalytic cracking of benzene

Catalytic decomposition is a very attractive way to convert tar components into H2, CO and other useful chemicals. The performance of Fe3Ni8/PG (palygorskite, PG) reduced in hydrogen at different temperatures for the catalytic decomposition of benzene has been assessed. Benzene was used as the model biomass tar. The effects of calcination atmosphere, temperatures and benzene concentration on catalytic cracking of benzene were measured. The results of XRD (X-Ray Diffraction), TEM (Transmission Electron Microscope), TPR (Temperature Program Reduction), TPSR (Temperature Program Surface Reduction), TC (Total Carbon), the reactivity component and reaction mechanism over Fe3Ni8/PG for catalytic cracking of benzene are discussed. The results showed particles of awaruite (Fe, Ni) about 2–30 nm were found on the surface of palygorskite by TEM when the calcination temperature was 600 °C. Particles with size smaller than 30 nm were obtained on all prepared Fe3Ni8/PG catalysts as shown by XRD. The nanoparticles proved to be the reactive component for catalytic cracking of benzene and the increase of active particle size caused the decrease in the reactivity of Fe3Ni8/PG. Fe3Ni8/PG annealed in hydrogen at 600 °C was proved to have the best reactivity in experiments (45% hydrogen yield). High concentration benzene (448 g/m3) accelerated the formation of carbon deposition. However, iron oxide decreases carbon deposition and increases the stability of catalyst for catalytic cracking of benzene. The application of Fe3Ni8/PG catalysts was proved a very effective catalyst for the catalytic cracking of benzene.

Sources of ultrafine particles and chemical species along a traffic corridor : comparison of the results from two receptor models

Particulate matter is common in our environment and has been linked to human health problems particularly in the ultrafine size range. A range of chemical species have been associated with particulate matter and of special concern are the hazardous chemicals that can accentuate health problems. If the sources of such particles can be identified then strategies can be developed for the reduction of air pollution and consequently, the improvement of the quality of life. In this investigation, particle number size distribution data and the concentrations of chemical species were obtained at two sites in Brisbane, Australia. Source apportionment was used to determine the sources (or factors) responsible for the particle size distribution data. The apportionment was performed by Positive Matrix Factorisation (PMF) and Principal Component Analysis/Absolute Principal Component Scores (PCA/APCS), and the results were compared with information from the gaseous chemical composition analysis. Although PCA/APCS resolved more sources, the results of the PMF analysis appear to be more reliable. Six common sources identified by both methods include: traffic 1, traffic 2, local traffic, biomass burning, and two unassigned factors. Thus motor vehicle related activities had the most impact on the data with the average contribution from nearly all sources to the measured concentrations higher during peak traffic hours and weekdays. Further analyses incorporated the meteorological measurements into the PMF results to determine the direction of the sources relative to the measurement sites, and this indicated that traffic on the nearby road and intersection was responsible for most of the factors. The described methodology which utilised a combination of three types of data related to particulate matter to determine the sources could assist future development of particle emission control and reduction strategies.

Vibrational spectroscopy of natural cave mineral monetite CaHPO4 and the synthetic analog

Monetite is a phosphate mineral formed by the reaction of the chemicals in bat guano with calcite substrates and is commonly found in caves. The analog of the mineral monetite CaHPO4 has been synthesized and the Raman and infrared spectra of the natural monetite originating from the Murra-el-elevyn Cave, Eucla, Western Australia, compared. Monetite is characterized by a complex set of phosphate bands that arise because of two sets of pairs of phosphate units in the unit cell. Raman and infrared bands are assigned to HPO4(2-), OH stretching and bending vibrations. Infrared bands at 1346 and 1402 cm−1 are assigned to POH deformation modes. Vibrational spectroscopy confirms the presence of monetite in the cave system.

Diabetes health program development for Aboriginal and Torres Strait Islander women

According to Australian Health (2008), the area of endocrine, nutritional and metabolic disorders (mainly diabetes) yields the highest cause of death for Indigenous Australian women at 10.1%. Indigenous Brisbane North women’s results reiterate this with slightly higher percentages and are a cause for concern and action due to the noted levels of undiagnosed/unaware Indigenous Brisbane North women with abnormal blood glucose levels, whom participated in the research. A sub-sample of the group (N=17) were piloted to test the feasibility of method of eliciting health information on Indigenous Women within this community. This pilot study revealed the following health information regarding this group of women. 41.2% of Indigenous Brisbane North women were found to have blood glucose levels that were outside normal ranges, however only 29.4% had been diagnosed with diabetes and or endocrine abnormalities. These findings highlight that 11.8% of participants have signs indicating that they may have undiagnosed diabetes or/and pre diabetes juxtaposed to unacceptable endocrine levels compatible with health and wellness. The percentages of Indigenous Brisbane North Women whom have indicated that they have a diagnosis of diabetes have been compared to both National Indigenous peoples percentages and the national percentages for the wider Australian community (all Australians). The rate of diabetes within this population is 9 times that of the wider Australian community and 5 times that of the wider Australian Indigenous community. Data was collected from Indigenous participants on arrival and the attendance numbers of 112 women was recorded for comparison with other current health prevention wellness programs being delivered. Data was also collected through the use of specially designed culturally safe questionnaires undertaken in conjunction with health checks and health service information given to participants.