Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells

The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8(+) T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8(+) T-cell infiltration of tumours and increase the efficacy of adoptive CD8(+) T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy ‘normalizes’ (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients

Fermi surface, possible unconventional fermions, and unusually robust resistive critical fields in the chiral-structured superconductor AuBe

The noncentrosymmetric superconductor (NCS) AuBe is investigated using a variety of thermodynamic and resistive probes in magnetic fields of up to 65~T and temperatures down to 0.3~K. Despite the polycrystalline nature of the samples, the observation of a complex series of de Haas-van Alphen (dHvA) oscillations has allowed the calculated bandstructure for AuBe to be validated. This permits a variety of BCS parameters describing the superconductivity to be estimated, despite the complexity of the measured Fermi surface. In addition, AuBe displays a nonstandard field dependence of the phase of dHvA oscillations associated with a band thought to host unconventional fermions in this chiral lattice. This result demonstrates the power of the dHvA effect to establish the properties of a single band despite the presence of other electronic bands with a larger density of states, even in polycrystalline samples. In common with several other NCSs, we find that the resistive upper critical field exceeds that measured by heat capacity and magnetization by a considerable factor. We suggest that our data exclude mechanisms for such an effect associated with disorder, implying that topologically protected superconducting surface states may be involved

Designing engaging online behaviour change interventions: a proposed model of user engagement

Camille E. Short, Amanda L. Rebar, Ronald C. Plotnikoff, Corneel Vandelanott

Automatic evaluation stimuli - the most frequently used words to describe physical activity and the pleasantness of physical activity

Physical activity is partially regulated by non-conscious processes including automatic evaluations - the spontaneous affective reactions we have to physical activity that lead us to approach or avoid physical activity opportunities. A sound understanding of which words best represent the concepts of physical activity and pleasantness (as associated with physical activity) is needed to improve the measurement of automatic evaluations and related constructs (e.g., automatic self-schemas, attentional biases). The first aim of this study was to establish population-level evidence of the most common word stimuli for physical activity and pleasantness. Given that response latency measures have been applied to assess automatic evaluations of physical activity and exercise, the second aim was to determine whether people use the same behavior and pleasant descriptors for physical activity and exercise. Australian adults (N = 1,318; 54.3% women; 48.9% aged 55 years or older) were randomly assigned to one of two groups, through a computer-generated 1:1 ratio allocation, to be asked to list either five behaviors and pleasant descriptors of physical activity (n = 686) or of exercise (n = 632). The words were independently coded twice as to whether they were novel words or the same as another (i.e., same stem or same meaning). Intercoder reliability varied between moderate and strong (agreement = 50.1 to 97.8%; κ = 0.48 to 0.82). A list of the 20 most common behavior and pleasantness words were established based on how many people reported them, weighted by the ranking (1-5) people gave them. The words people described as physical activity were mostly the same as those people used to describe exercise. The most common behavior words were 'walking,' 'running,' 'swimming,' 'bike riding,' and 'gardening'; and the most common pleasant descriptor words were 'relaxing,' 'happiness,' 'enjoyment,' 'exhilarating,' 'exhausting,' and 'good.' These sets of stimuli can be utilized as resources for response latency measurement tasks of automatic evaluations and for tools to enhance automatic evaluations of physical activity in evaluative conditioning tasks.Amanda L. Rebar, Stephanie Schoeppe, Stephanie J. Alley, Camille E. Short, James A. Dimmock, Ben Jackson, David E. Conroy, Ryan E. Rhodes and Corneel Vandelanott

Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large‐scale deletions or point mutations

We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site‐specific elimination of pathogenic human mitochondrial DNA (mtDNA). We used mtZFNs to target and cleave mtDNA harbouring the m.8993T>G point mutation associated with neuropathy, ataxia, retinitis pigmentosa (NARP) and the “common deletion” (CD), a 4977‐bp repeat‐flanked deletion associated with adult‐onset chronic progressive external ophthalmoplegia and, less frequently, Kearns‐Sayre and Pearson's marrow pancreas syndromes. Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild‐type mtDNA restored mitochondrial respiratory function in a CD cybrid cell model. This study constitutes proof‐of‐principle that, through heteroplasmy manipulation, delivery of site‐specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species

Validity and responsiveness to change of the Active Australia Survey according to gender, age, BMI, education, and physical activity level and awareness

© 2019 The Author(s). Background: This study aimed to investigate the validity of the Active Australia Survey across different subgroups and its responsiveness to change, as few previous studies have examined this. Methods: The Active Australia Survey was validated against the ActiGraph as an objective measure of physical activity. Participants (n = 465) wore the ActiGraph for 7 days and subsequently completed the Active Australia Survey. Moderate activity, vigorous activity and total moderate and vigorous physical activity were compared using Spearman rank-order correlations. Changes in physical activity between baseline and 3-month assessments were correlated to examine responsiveness to change. The data were stratified to assess outcomes according to different subgroups (e.g., gender, age, weight, activity levels). Results: With regards to the validity, a significant correlation of ρ = 0.19 was found for moderate physical activity, ρ = 0.33 for vigorous physical activity and ρ = 0.23 for moderate and vigorous physical activity combined. For vigorous physical activity correlations were higher than 0.3 for most subgroups, whereas they were only higher than 0.3 in those with a healthy weight for the other activity outcomes. With regards to responsiveness to change, a correlation of ρ = 0.32 was found for moderate physical activity, ρ = 0.19 for vigorous physical activity and ρ = 0.35 for moderate and vigorous physical activity combined. For moderate and vigorous activity combined correlations were higher than 0.4 for several subgroups, but never for vigorous physical activity. Conclusions: Little evidence for the validity of Active Australia Survey was found, although the responsiveness to change was acceptable for several subgroups. Findings from studies using the Active Australia Survey should be interpreted with caution. Trial registration: World Health Organisation Universal Trial Number: U111-1119-1755. Australian New Zealand Clinical Trials Registry, ACTRN12611000157976. Registration date: 8 March 2011

Transduction of artificial transcriptional regulatory proteins into human cells

Protein transduction (PT) is a method for delivering proteins into mammalian cells. PT is accomplished by linking a small peptide tag—called a PT domain (PTD)—to a protein of interest, which generates a functional fusion protein that can penetrate efficiently into mammalian cells. In order to study the functions of a transcription factor (TF) of interest, expression plasmids that encode the TF often are transfected into mammalian cells. However, the efficiency of DNA transfection is highly variable among different cell types and is usually very low in primary cells, stem cells and tumor cells. Zinc-finger transcription factors (ZF-TFs) can be tailor-made to target almost any gene in the human genome. However, the extremely low efficiency of DNA transfection into cancer cells, both in vivo and in vitro, limits the utility of ZF-TFs. Here, we report on an artificial ZF-TF that has been fused to a well-characterized PTD from the human immunodeficiency virus-1 (HIV-1) transcriptional activator protein, Tat. This ZF-TF targeted the endogenous promoter of the human VEGF-A gene. The PTD-attached ZF-TF was delivered efficiently into human cells in vitro. In addition, the VEGF-A-specific transcriptional repressor retarded the growth rate of tumor cells in a mouse xenograft experiment

Physical activity screening to recruit inactive randomized controlled trial participants: how much is too much?

Citation: Vandelanotte, C., Stanton, R., Rebar, A. L., Van Itallie, A. K., Caperchione, C. M., Duncan, M. J., . . . Kolt, G. S. (2015). Physical activity screening to recruit inactive randomized controlled trial participants: how much is too much? Trials, 16, 3. doi:10.1186/s13063-015-0976-7Screening physical activity levels is common in trials to increase physical activity in inactive populations. Commonly applied single-item screening tools might not always be effective in identifying those who are inactive. We applied the more extensive Active Australia Survey to identify inactive people among those who had initially been misclassified as too active using a single-item measure. Those enrolled after the Active Australia Survey screening had significantly higher physical activity levels at subsequent baseline assessment. Thus, more extensive screening measures might result in the inclusion of participants who would otherwise be excluded, possibly introducing unwanted bias

How is adults' screen time behaviour influencing their views on screen time restrictions for children? A cross-sectional study

Published: 1 March 2016High screen time in children and its detrimental health effects is a major public health problem. How much screen time adults think is appropriate for children remains little explored, as well as whether adults' screen time behaviour would determine their views on screen time restrictions for children. This study aimed to investigate how adults' screen time behaviour influences their views on screen time restrictions for children, including differences by gender and parental status.In 2013, 2034 Australian adults participated in an online survey conducted by the Population Research Laboratory at Central Queensland University, Rockhampton. Adult screen time behaviour was assessed using the Workforce Sitting Questionnaire. Adults reported the maximum time children aged between 5-12 years should be allowed to spend watching TV and using a computer. Ordinal logistic regression was used to compare adult screen time behaviour with views on screen time restrictions for children.Most adults (68 %) held the view that children should be allowed no more than 2 h of TV viewing and computer use on school days, whilst fewer adults (44 %) thought this screen time limit is needed on weekend days. Women would impose higher screen time restrictions for children than men (p  2 h on watching TV and using the computer at home on work days (66 %) and non-work days (88 %). Adults spending ≤ 2 h/day in leisure-related screen time were less likely to permit children > 2 h/day of screen time. These associations did not differ by adult gender and parental status.Most adults think it is appropriate to limit children's screen time to the recommended ≤ 2 h/day but few adults themselves adhere to this screen time limit. Adults with lower screen use may be more inclined to limit children's screen time. Strategies to reduce screen time in children may also need to target adult screen use.Stephanie Schoeppe, Amanda L. Rebar, Camille E. Short, Stephanie Alley, Wendy Van Lippevelde and Corneel Vandelanott

Evolutionary change in the construction of the nursery environment when parents are prevented from caring for their young directly.

Funder: EC | FP7 | FP7 Ideas: European Research Council (FP7 Ideas); Id: 100011199; Grant(s): 310785Parental care can be partitioned into traits that involve direct engagement with offspring and traits that are expressed as an extended phenotype and influence the developmental environment, such as constructing a nursery. Here, we use experimental evolution to test whether parents can evolve modifications in nursery construction when they are experimentally prevented from supplying care directly to offspring. We exposed replicate experimental populations of burying beetles (Nicrophorus vespilloides) to different regimes of posthatching care by allowing larvae to develop in the presence (Full Care) or absence of parents (No Care). After only 13 generations of experimental evolution, we found an adaptive evolutionary increase in the pace at which parents in the No Care populations converted a dead body into a carrion nest for larvae. Cross-fostering experiments further revealed that No Care larvae performed better on a carrion nest prepared by No Care parents than did Full Care larvae. We conclude that parents construct the nursery environment in relation to their effectiveness at supplying care directly, after offspring are born. When direct care is prevented entirely, they evolve to make compensatory adjustments to the nursery in which their young will develop. The rapid evolutionary change observed in our experiments suggests there is considerable standing genetic variation for parental care traits in natural burying beetle populations-for reasons that remain unclear