Constitutive behavior of as-cast A356

The constitutive behavior of aluminum alloy A356 in the as-cast condition has been characterized using compression tests performed over a wide range of deformation temperatures (30-500{\deg}C) and strain rates (\approx0.1-10 /s). This work is intended to support the development of process models for a wide range of conditions including those relevant to casting, forging and machining. The flow stress behavior as a function of temperature and strain rate has been fit to a modified Johnson-Cook and extended Ludwik-Hollomon expression. The data has also been assessed with both the strain-independent Kocks-Mecking and Zener-Hollomon frameworks. The predicted plastic flow stress for each expression are compared. The results indicate that the extended Ludwik-Hollomon is best suited to describe small strain conditions (stage III hardening), while the Kocks-Mecking is best employed for large strain (stage IV). At elevated temperatures, it was found that the Zener-Hollomon model provides the best prediction of flow stress.Comment: 34 pages, 12 figure

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Non-Immersive Virtual Reality Exercise Can Increase Exercise in Older Adults Living in the Community and in Long-Term Care: A Randomized Controlled Trial

Lisa Sheehy,1 Lalita Bharadwaj,2 Kelsey Annie Nissen,2 Justine L Estey2 1Bruyère Health Research Institute, Ottawa, Ontario, Canada; 2Centre for Innovation and Research in Aging, Fredericton, New Brunswick, CanadaCorrespondence: Lisa Sheehy, Bruyère Health Research Institute, 43 Bruyère St, Ottawa, ON, K1N 5C8, Canada, Tel +01 613 562 6262 ext. 1593, Email [email protected]: To assess the impact of an 8-week non-immersive virtual reality exercise program for older adults on 1) balance, physical function, community integration and quality of life; 2) falls, emergency room visits, hospital and long-term care admissions; 3) quantity of exercise performed; and 4) acceptance of non-immersive virtual reality.Patients and Methods: This prospective, assessor-blinded, randomized controlled trial was carried out on two separate samples of older adults: those living in their own homes (“home-based”) and those living in long-term care (“facility-based”). Participants were randomized to non-immersive virtual reality or usual activity. Non-immersive virtual reality consisted of 20– 30 minutes of customized, gamified exercises for balance, stepping, strengthening, and aerobic conditioning, performed 3– 5x/week for 8 weeks. Outcomes were measured before the intervention, immediately after, and 1 month later. Physical testing and questionnaires addressed objective 1). Counts for objectives 2) and 3) were reported by the participants and retrieved from the non-immersive virtual reality platform. Logbooks and a short interview addressed objective 4).Results: Recruitment was substantially impacted by the COVID-19 pandemic. The facility-based sample had 31 participants; the home-based sample had 16. There were no statistically-significant benefits to non-immersive virtual reality in either sample for objective 1), although the facility-based non-immersive virtual reality group showed a clinically-significant improvement in functional walking. Effect sizes were small (≤ 0.16). No falls occurred during non-immersive virtual reality exercise. The facility-based non-immersive virtual reality group did an average of 14.1 sessions (average 20.1 minutes/session) and the home-based non-immersive virtual reality group did an average of 17.2 sessions (22.6 minutes/session). Participants enjoyed the non-immersive virtual reality, found it challenging and motivating and felt that it improved balance and walking. Most were interested to continue beyond the study.Conclusion: Non-immersive virtual reality for home-based and facility-based older adults is safe, enjoyable and feasible and may increase users’ weekly levels of physical activity leading to clinical benefits for functional walking in facility-based users.Trial Registration: ClinicalTrials.gov (NCT04083885; registered 2019– 09-06).Plain language summary: Regular exercise is so important for older adults. It improves strength, flexibility, endurance and balance, reduces the risk of falls, and increases independence. However, many older adults do not exercise, for a variety of reasons. We tested a fun and safe way for seniors to do a customized exercise program in their own home, using a non-immersive virtual reality platform called Jintronix, which turns exercise into games!We recruited older adults living in their own homes (home-based sample), and those living in long-term care (facility-based sample) to try the exercise program for 20-30 minutes, 3-5 times a week for 8 weeks. The exercises were customized to each participant by a therapist, who followed up weekly.A total of 47 participants were recruited. The 16 home-based participants did an average of 17 sessions (23 min/session) over the 8 weeks, and the 31 facility-based participants did an average of 14 sessions (20 min/session). The sessions were safe – no one fell or sustained significant injury while doing non-immersive virtual reality exercise. Participants enjoyed the program and found it challenging and motivating, and commented that it improved their balance and walking. Most participants wished to continue once the study was over.We have confirmed that non-immersive virtual reality exercise can engage older adults to exercise more, with the potential to improve their health and independence. This exercise option is ideal for older adults who find it difficult to leave their home or wish to exercise privately.Keywords: exergaming, older adults, healthy agin

Anxiety and Depression in Adults with Autism Spectrum Disorder: A Systematic Review and Meta-analysis

Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety (n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression (n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Riding the knowledge translation roundabout: lessons learned from the Canadian Institutes of Health Research Summer Institute in knowledge translation

<p>Abstract</p> <p>Background</p> <p>Funding the education and training of the next generation of health researchers is a key mandate of the Canadian Institutes of Health Research (CIHR) knowledge translation (KT) portfolio. The field of KT is growing daily; thus, the training and development of a new generation of KT researchers is essential.</p> <p>Methods</p> <p>Using curriculum documents, participant evaluations, and self-reflection, this paper describes a unique Summer Institute hosted by the CIHR in Cornwall, Ontario, Canada. We outline the key aspects of a successful training initiative that could inform organizations and agencies worldwide with an interest in or who have a mandate for KT.</p> <p>Results</p> <p>This work provides potential funders, faculty, and students with an inside look into the purpose, process, and outcomes of such training initiatives.</p> <p>Conclusion</p> <p>National and international KT organizations, research institutions, and funding agencies are encouraged to consider replicating the training model employed here, as investment into KT personnel will foster the advancement of the field within and beyond local borders.</p> <p>'To the individual who devotes his/her life to science, nothing can give more happiness than when the results immediately find practical application. There are not two sciences. There is science and the application of science, and these two are linked as the fruit is to the tree.' – Louis Pasteur, 1871 (from presentation by Ian Graham, 2008 CIHR Knowledge Translation Summer Institute)</p

Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals

Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism