1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1α,25 dihydroxyvitamin D₃(1,25(OH)₂D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown.</p> <p>Results</p> <p>We examined the effect of 1,25(OH)₂D (+/- 100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)₂D (Affymetrix U133 Plus 2.0, n = 4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60% up), 48 h, 3566 (38% up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e.g. IL-1 pathway) and suppression of proinflammatory pathways continued at later time points (e.g. IL-17 and IL-6 pathways). There was also evidence for induction of anti-angiogenic pathways and induction of transcripts for protection from oxidative stress or maintenance of cell redox homeostasis at 6 h.</p> <p>Conclusions</p> <p>Our data reveal of large number of potential new, direct vitamin D target genes relevant to prostate cancer prevention. In addition, our data suggests that rather than having a single strong regulatory effect, vitamin D orchestrates a pattern of changes within prostate epithelial cells that limit or slow carcinogenesis.</p

Tedera: From a Promising Novel Species to a Commercial Pasture Option for Mediterranean Southern Australia

Tedera (Bituminaria bituminosa var. albomarginata and var. crassiuscula) is a traditional forage species used for centuries in the Canary Islands (Méndez and Fernández 1990), that has increasingly attracted interest from researchers in regions with Mediterranean-type climates from Spain, Italy, Israel, Greece, Portugal, Morocco, Turkey and Australia. In 2000, Australian pasture researchers started a large and systematic screening process that evaluated about 720 species of exotic and native legumes, grasses and herbs for adaptation and productivity in Mediterranean and temperate environments (Real et al. 2011). Tedera was one of the few novel perennial legumes to show potential for domestication (Real et al. 2008; Real et al. 2011). Now an international multidisciplinary team has come together to take tedera forward towards commercial adoption by farmers in Mediterranean-type environments. This paper provides a technical update and discussion on all research aspects conducted by the tedera research team up to February 2013

ERK2 alone drives inflammatory pain but cooperates with ERK1 in sensory neuron survival

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP-mediated deletion of ERK2 in Na(v)1.8(+) sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Na(v)1.8(+) sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons. SIGNIFICANCE STATEMENT ERK1/2 signaling affects sensory neuron function and survival. However, it was not clear whether ERK isoform-specific roles exist in these processes postnatally. Previous work from our laboratory suggested either functional redundancy of ERK isoforms or a predominant role for ERK2 in pain; however, the tools to discriminate between these possibilities were not available at the time. In the present study, we use new genetic knock-out lines to demonstrate that ERK2 in sensory neurons is necessary for development of inflammatory pain and for postnatal maintenance of peptidergic epidermal innervation. Interestingly, postnatal loss of both ERK isoforms leads to a profound loss of sensory neurons. Therefore, ERK1 and ERK2 display both functionally distinct and redundant roles in sensory neurons

Crop Updates 2005 - Katanning

This session covers twenty five papers from different authors KEYNOTE How Farmers Can Work Together for a More Sustainable and Profitable Business, Brian McAlpine Farmer, Nuffield Scholar GENERAL 2005 Seasonal Outlook, David Stephens and Nicola Telcik, Department of Agriculture Essentials for cereal leaf disease management, K. Jayasena, R. Loughman, G. Thomas, C. Beard, and B. Paynter, Department of Agriculture Benefits to the grower of grain licensing, Colin Mann, Grain Licensing Authority SOIL & NUTRIENTS The effect of higher nitrogen fertiliser prices on rotation and fertiliser strategies in cropping systems, Ross Kingwell, Department of Agriculture Effect of stubble burning and seasonality on microbial processes and nutrient cycling, Francis Hoyle, University of Western Australia Soil Biology and Crop Production in Western Australian Farming Systems, D.V. Murphy, N. Milton, M. Osman, F.C. Hoyle, L.K Abbott, W.R. Cookson and S. Darmawanto, University of Western Australia Nutrient Management to get optimal production, Bill Bowden, Department of Agriculture OTHER CROPS Which malting barley variety and why? Blakely Paynter, Department of Agriculture KASPA AND OTHER NEW PULSE VARIETIES, 1. New Pulse varieties and where they fit in, K. Regan, P. White, Department of Agriculture & CLIMA, K. Siddique, CLIMA, K. Adhikari, Department of Agriculture & CLIMA, M. Harries, CLIMA Kaspa in the WA Grain Belt 2003-2004, Ian Pritchard, Department of Agriculture New annual pastures for Mediterranean farming systems, Angelo Loi, Phil Nichols, Clinton Revell & David Ferris, Department of Agriculture Challenging herbicide resistant ryegrass, Bill Roy, Agricultural Consulting & Research Services Pty.Ltd WEED MANAGEMENT Ingest, incinerate or invert? The pro’s and con’s of 3 weed seed removal tactics, Sally Peltzer1, Dave Minkey1 and Michael Walsh2 Department of Agriculture 1 and Western Australian Herbicide Resistance lnitiative2 A good use guide for pre-emergent herbicides, Alexandra Douglas, Department of Agriculture OTHER USEFUL INFORMATION 17.Growing season outlook, Meredith Fairbanks, Ian Foster, Geraldine Pasqual, David Stephens, Nicola Telcik, David Tennant, Department of Agriculture 18. Status Of Department Of Agriculture Western Australia Crop Varieties 19. Seed Licensee Details 20. Gene technology for growers. What is it? How does it Work? Belinda Barr, Australian Centre for Plant Functional Genomics, Dr Heather Bray, Molecular Plant Breeding Cooperative Research Centre. 21. Agronomic package for EGA Eagle Rock, Steve Penny, Department of Agriculture 22. Nutrient timing and requirements for increased crop yields in the high rainfall cropping zone, Narelle Hill, Ron McTaggart, Dr. Wal Anderson and Ray Tugwell Department of Agriculture 23. Insect contamination of cereal grain at harvest, Svetlana Micic and Phil Michael, Department of Agriculture 24. Crop leftovers: what’s in stubble for sheep? Roy Butler and Keith Croker, Department of Agriculture 25. Mandelup – Narrow-leafed lupi

Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes

BACKGROUND: Obesity and type 2 diabetes (T2DM) are associated with increased circulating free fatty acids and triacylglycerols. However, very little is known about specific molecular lipid species associated with these diseases. In order to gain further insight into this, we performed plasma lipidomic analysis in a rodent model of obesity and insulin resistance as well as in lean, obese and obese individuals with T2DM. METHODOLOGY/PRINCIPAL FINDINGS: Lipidomic analysis using liquid chromatography coupled to mass spectrometry revealed marked changes in the plasma of 12 week high fat fed mice. Although a number of triacylglycerol and diacylglycerol species were elevated along with of a number of sphingolipids, a particularly interesting finding was the high fat diet (HFD)-induced reduction in lysophosphatidylcholine (LPC) levels. As liver, skeletal muscle and adipose tissue play an important role in metabolism, we next determined whether the HFD altered LPCs in these tissues. In contrast to our findings in plasma, only very modest changes in tissue LPCs were noted. To determine when the change in plasma LPCs occurred in response to the HFD, mice were studied after 1, 3 and 6 weeks of HFD. The HFD caused rapid alterations in plasma LPCs with most changes occurring within the first week. Consistent with our rodent model, data from our small human cohort showed a reduction in a number of LPC species in obese and obese individuals with T2DM. Interestingly, no differences were found between the obese otherwise healthy individuals and the obese T2DM patients. CONCLUSION: Irrespective of species, our lipidomic profiling revealed a generalized decrease in circulating LPC species in states of obesity. Moreover, our data indicate that diet and adiposity, rather than insulin resistance or diabetes per se, play an important role in altering the plasma LPC profile

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Multi-Modality Imaging in Vasculitis

Systemic vasculitides are a rare and complex group of diseases that can affect multiple organ systems. Clinically, presentation may be vague and non-specific and as such, diagnosis and subsequent management are challenging. These entities are typically classified by the size of vessel involved, including large-vessel vasculitis (giant cell arteritis, Takayasu’s arteritis, and clinically isolated aortitis), medium-vessel vasculitis (including polyarteritis nodosa and Kawasaki disease), and small-vessel vasculitis (granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis). There are also other systemic vasculitides that do not fit in to these categories, such as Behcet’s disease, Cogan syndrome, and IgG4-related disease. Advances in medical imaging modalities have revolutionized the approach to diagnosis of these diseases. Specifically, color Doppler ultrasound, computed tomography and angiography, magnetic resonance imaging, positron emission tomography, or invasive catheterization as indicated have become fundamental in the work up of any patient with suspected systemic or localized vasculitis. This review presents the key diagnostic imaging modalities and their clinical utility in the evaluation of systemic vasculitis

Alpine Russet: A Potato Cultivar Having Long Tuber Dormancy Making it Suitable for Processing from Long-term Storage

Abstract Alpine Russet is a later maturing, oblong-long, lightly russeted potato cultivar, notable for having tuber dormancy comparable to Russet Burbank. Processing quality of Alpine Russet from long-term storage is superior to Russet Burbank, with low percent reducing sugars and uniform fry color due to a low percentage difference of sugars between the bud and stem ends. Alpine Russet yields were comparable to Russet Burbank in early harvest trials and were comparable or significantly larger in late harvest trials depending on the location. At two late season locations, Alpine Russet had the largest total and percent No. 1 yields and the largest percent mid-range No. 1 tubers compared to Ranger Russet and Russet Burbank. It has moderately high specific gravity and is resistant to most external and internal defects. Alpine Russet has been evaluated in public and industry trials throughout the Western U.S. for over 15 years. Resumen Alpine Russet es una variedad de papa de madures tardía, larga-oblonga, ligeramente como Russet, notable por tener una dormancia del tubérculo comparable a Russet Burbank. La calidad de procesamiento de Alpine Russet después de un almacenamiento prolongado es superior a Russet Burbank, con bajo porcentaje de azúcares reductores y color uniforme de freído debido a la baja diferencia en porcentaje de azúcares entre la yema apical y la base. Los rendimientos de Alpine Russet fueron comparables a Russet Burbank en ensayos de cosecha temprana y fueron comparables o significativamente mayores en ensayos de cosecha tardía, dependiendo del lugar. En dos lugares de ciclo tardío, Alpine Russet tuvo los mayores rendimientos totales y en porcentaje de No. 1, y el mayor porcentaje de tubérculos de amplitud media No. 1 comparada con Ranger Russet y Russet Burbank. Tiene moderadamente alta gravedad específica y es resistente a la mayoría de los defectos externos e internos. Alpine Russet ha sido evaluada en ensayos públicos y de la industria a lo largo del oeste de los E.U. por más de 15 años