44 research outputs found
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Targeting HOX transcription factors in prostate cancer
YesBackground: The HOX genes are a family of transcription factors that help to determine cell and tissue identity
during early development, and which are also over-expressed in a number of malignancies where they have been
shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX
genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor
of HOX function.
Methods: HOX function was inhibited using the HXR9 peptide. HOX gene expression was assessed by RNA
extraction from cells or tissues followed by quantitative PCR, and siRNA was used to block the expression of the
HOX target gene, cFos. In vivo modelling involved a mouse flank tumour induced by inoculation with LNCaP cells.
Results: In this study we show that the expression of HOX genes in prostate tumours is greatly increased with
respect to normal prostate tissue. Targeting the interaction between HOX proteins and their PBX cofactor induces
apoptosis in the prostate cancer derived cell lines PC3, DU145 and LNCaP, through a mechanism that involves a
rapid increase in the expression of cFos, an oncogenic transcription factor. Furthermore, disrupting HOX/PBX
binding using the HXR9 antagonist blocks the growth of LNCaP tumours in a xenograft model over an extended
period.
Conclusion: Many HOX genes are highly over-expressed in prostate cancer, and prostate cancer cells are sensitive
to killing by HXR9 both in vitro and in vivo. The HOX genes are therefore a potential therapeutic target in prostate
cancer.The authors gratefully acknowledge the support of the Prostate Project charity (UK)
Crop Updates 2006 - Cereals
This session covers twenty nine papers from different authors:
PLENARY
1. The 2005 wheat streak mosaic virus epidemic in New South Wales and the threat posed to the Western Australian wheat industry, Roger Jones and Nichole Burges, Department of Agriculture
SOUTH COAST AGRONOMY
2. South coast wheat variety trial results and best options for 2006, Mohammad Amjad, Ben Curtis and Wal Anderson, Department of Agriculture
3. Dual purpose winter wheats to improve productivity, Mohammad Amjad and Ben Curtis, Department of Agriculture
4. South coast large-scale premium wheat variety trials, Mohammad Amjad and Ben Curtis, Department of Agriculture
5. Optimal input packages for noodle wheat in Dalwallinu â Liebe practice for profit trial, Darren Chitty, Agritech Crop Research and Brianna Peake, Liebe Group
6. In-crop risk management using yield prophetÂź, Harm van Rees1, Cherie Reilly1, James Hunt1, Dean Holzworth2, Zvi Hochman2; 1Birchip Cropping Group, Victoria; 2CSIRO, Toowoomba, Qld
7. Yield ProphetÂź 2005 â On-line yield forecasting, James Hunt1, Harm van Rees1, Zvi Hochman2,Allan Peake2, Neal Dalgliesh2, Dean Holzworth2, Stephen van Rees1, Trudy McCann1 and Peter Carberry2; 1Birchip Cropping Group, Victoria; 2CSIRO, Toowoomba, Qld
8. Performance of oaten hay varieties in Western Australian environments, Raj Malik and Kellie Winfield, Department of Agriculture
9. Performance of dwarf potential milling varieties in Western Australian environments, Kellie Winfield and Raj Malik, Department of Agriculture
10. Agronomic responses of new wheat varieties in the Southern agricultural region of WA, Brenda Shackley and Judith Devenish, Department of Agriculture
11. Responses of new wheat varieties to management factors in the central agricultural region of Western Australia, Darshan Sharma, Steve Penny and Wal Anderson,Department of Agriculture
12. Sowing time on wheat yield, quality and $ - Northern agricultural region, Christine Zaicou-Kunesch, Department of Agriculture
NUTRITION
13.The most effective method of applying phosphorus, copper and zinc to no-till crops, Mike Bolland and Ross Brennan, Department of Agriculture
14. Uptake of K from the soil profile by wheat, Paul Damon and Zed Rengel, Faculty of Natural and Agricultural Sciences, University of Western Australia
15. Reducing nitrogen fertiliser risks, Jeremy Lemon, Department of Agriculture
16. Yield ProphetÂź and canopy management, Harm van Rees1, Zvi Hochman2, Perry Poulton2, Nick Poole3, Brooke Thompson4, James Hunt1; 1Birchip Cropping Group, Victoria; 2CSIRO, Toowoomba, Qld; 3Foundation for Arable Research, New Zealand; 4Cropfacts, Victoria
17. Producing profits with phosphorus, Stephen Loss, CSBP Ltd, WA
18. Potassium response in cereal cropping within the medium rainfall central wheatbelt, Jeff Russell1, Angie Roe2 and James Eyres2, Department of Agriculture1, Farm Focus Consultants, Northam2
19. Matching nitrogen supply to wheat demand in the high rainfall cropping zone, Narelle Simpson, Ron McTaggart, Wal Anderson, Lionel Martin and Dave Allen, Department of Agriculture
DISEASES
20. Comparative study of commercial wheat cultivars and differential lines (with known Pm resistance genes) to powdery mildew response, Hossein Golzar, Manisha Shankar and Robert Loughman, Department of Agriculture
21. On farm research to investigate fungicide applications to minimise leaf disease impacts in wheat â part II, Jeff Russell1, Angie Roe2and James Eyres2, Department of Agriculture1, and Farm Focus Consultants, Northam2
22. Disease resistance update for wheat varieties in WA, Manisha Shankar, John Majewski, Donna Foster, Hossein Golzar, Jamie Piotrowski, Nicole Harry and Rob Loughman, Department of Agriculture
23. Effect of time of stripe rust inoculum arrival on variety response in wheat, Manisha Shankar, John Majewski and Rob Loughman, Department of Agriculture
24. Fungicide seed dressing management of loose smut in Baudin barley, Geoff Thomas and Kith Jayasena, Department of Agriculture
PESTS
25. How to avoid insect contamination in cereal grain at harvest, Svetlana Micic, Paul Matson and Tony Dore, Department of Agriculture
ABIOTIC
26. Environment â is it as important as variety in sprouting tolerance? Thomas (Ben) Biddulph1, Dr Daryl Mares1, Dr Julie Plummer1 and Dr Tim Setter2, School of Plant Biology, University of Western Australia1 and Department of Agriculture2
27. Frost or fiction, Garren Knell, Steve Curtin and Wade Longmuir, ConsultAg Pty Ltd, WA
28. High moisture wheat harvesting in Esperance 2005, Nigel Metz, South East Premium Wheat Growers Association (SEPWA) Projects Coordinator, Esperance, WA
SOILS
28. Hardpan penetration ability of wheat roots, Tina Botwright Acuña and Len Wade, School of Plant Biology, University of Western Australia
MARKETS
29. Crop shaping to meet predicted market demands for wheat in the 21st Century, Cindy Mills and Peter Stone,Australian Wheat Board, Melbourn
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, PÂ =Â 1.65Â ĂÂ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PÂ =Â 2.3Â ĂÂ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PÂ =Â 3.98Â ĂÂ Â 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PÂ =Â 4.99Â ĂÂ 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Mental Representations of Weekdays
Keeping social appointments involves keeping track of what day it is. In practice, mismatches between apparent day and actual day are common. For example, a person might think the current day is Wednesday when in fact it is Thursday. Here we show that such mismatches are highly systematic, and can be traced to specific properties of their mental representations. In Study 1, mismatches between apparent day and actual day occurred more frequently on midweek days (Tuesday, Wednesday, and Thursday) than on other days, and were mainly due to intrusions from immediately neighboring days. In Study 2, reaction times to report the current day were fastest on Monday and Friday, and slowest midweek. In Study 3, participants generated fewer semantic associations for "Tuesday", "Wednesday" and "Thursday" than for other weekday names. Similarly, Google searches found fewer occurrences of midweek days in webpages and books. Analysis of affective norms revealed that participants' associations were strongly negative for Monday, strongly positive for Friday, and graded over the intervening days. Midweek days are confusable because their mental representations are sparse and similar. Mondays and Fridays are less confusable because their mental representations are rich and distinctive, forming two extremes along a continuum of change
Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science
It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the âSeattle Implementation Research Conferenceâ; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRCâs membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRCâs primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term âEBP championsâ for these groups) â and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleaguesâ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570