The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation

Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers. PLK1 inhibition is a promising therapeutic strategy and works by arresting cells in mitosis due to monopolar spindles. The p53 tumour suppressor protein is a short-lived transcription factor that can inhibit the growth, or stimulate the death, of developing cancer cells. Curiously, although p53 normally acts in an anti-cancer capacity, it can offer significant protection against inhibitors of PLK1, but the events underpinning this effect are not known. Here, we show that functional p53 reduces the sensitivity to PLK1 inhibitors by permitting centrosome separation to occur, allowing cells to traverse mitosis and re-enter cycle with a normal complement of 2N chromosomes. Protection entails the activation of p53 through the DNA damage-response enzymes, ATM and ATR, and requires the phosphorylation of p53 at the key regulatory site, Ser15. These data highlight a previously unrecognised link between p53, PLK1 and centrosome separation that has therapeutic implications for the use of PLK1 inhibitors in the clinic

Ocular accommodation and cognitive demand: An additional indicator besides pupil size and cardiovascular measures?

<p>Abstract</p> <p>Background</p> <p>The aim of the present study was to assess accommodation as a possible indicator of changes in the autonomic balance caused by altered cognitive demand. Accounting for accommodative responses from a human factors perspective may be motivated by the interest of designing virtual image displays or by establishing an autonomic indicator that allows for remote measurement at the human eye. Heart period, pulse transit time, and the pupillary response were considered as reference for possible closed-loop accommodative effects. Cognitive demand was varied by presenting monocularly numbers at a viewing distance of 5 D (20 cm) which had to be read, added or multiplied; further, letters were presented in a "n-back" task.</p> <p>Results</p> <p>Cardiovascular parameters and pupil size indicated a change in autonomic balance, while error rates and reaction time confirmed the increased cognitive demand during task processing. An observed decrease in accommodation could not be attributed to the cognitive demand itself for two reasons: (1) the cognitive demand induced a shift in gaze direction which, for methodological reasons, accounted for a substantial part of the observed accommodative changes. (2) Remaining effects disappeared when the correctness of task processing was taken into account.</p> <p>Conclusion</p> <p>Although the expectation of accommodation as possible autonomic indicator of cognitive demand was not confirmed, the present results are informative for the field of applied psychophysiology noting that it seems not to be worthwhile to include closed-loop accommodation in future studies. From a human factors perspective, expected changes of accommodation due to cognitive demand are of minor importance for design specifications – of, for example, complex visual displays.</p

Musculoskeletal pain experienced on most days is a common accompaniment of ageing amongst community-dwelling older Australians: a questionnaire-based study

Objective: To describe the prevalence, location and impact of moderate to severe pain experienced on most days in community-dwelling older (≥70 years) adults who were ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial participants. Methods: Cross-sectional ASPREE Longitudinal Study of Older Persons (ALSOP) data were collected from self-reported questionnaires administered to 16,439 ASPREE participants. Results: Of 14,155 respondents, 41% of males (n = 2651/6475) and 50% of females (n = 3803/7680) reported experiencing pain on most days. One quarter of respondents reported experiencing pain on most days that was moderate or severe in intensity (n = 3560/14,155), commonly located in the lower back, knees and upper back. Of those reporting moderate or severe pain, 51% reported taking analgesic medication on most days (n = 1812/3560), almost one-third also reported regular interference with sleep (29%, n = 1024/3560), walking (35%, n = 1239/3560) and daily activities (41%, n = 1467/3560). Discussion: Lower back, knee or upper back pain is a common accompaniment of ageing

Evaluation of the Pain Impact Index for Community-Dwelling Older Adults Through the Application of Rasch Modelling

Objective: Evaluate the Pain Impact Index, a simple, brief, easy-to-use, and novel tool to assess the impact of chronic pain in community-dwelling older adults.Methods: A Rasch modelling analysis was undertaken in Stata using a partial credit model suited to the Likert-type items that comprised the Index. The Index was evaluated for ordering of category thresholds, unidimensionality, overall fit to the Rasch model, measurement bias (Differential Item Functioning, DIF), targeting, and construct validity.Results: The four-item Pain Impact Index was self-completed by 6454 community-dwelling Australians who were aged at least 70 years and experienced pain on most days. Two items showed evidence of threshold disordering, and this was resolved by collapsing response categories (from 5 to 3) for all items. The rescored Index conformed to the unidimensionality assumption and had satisfactory fit with the Rasch model (analyses conducted on a reduced sample size to mitigate the potential for overpowering: n = 377, P > 0.0125, power > 77%). When considering uniform DIF, the most frequent sources of measurement bias were age, knee pain, and upper back pain. When considering nonuniform DIF, the most frequent source of measurement bias was knee pain. The Index had good ability to differentiate between respondents with different levels of pain impact and had highest measurement precision for respondents located around the average level of pain impact in the study sample. Both convergent and discriminant validity of the Index were supported.Conclusion: The Pain Impact Index showed evidence of unidimensionality, was able to successfully differentiate between levels of pain impact, and had good evidence of construct validity

Moderate or severe low back pain is associated with body mass index amongst community-dwelling older Australians

Objective: Low back pain is prevalent in older populations and modifiable risk factors may include being overweight or obese. This study aimed to describe the prevalence and impact of moderate or severe low back pain in community-dwelling older adults and its association with body mass index (BMI). Methods: Cross-sectional study involving 16,439 Australians aged ≥70 years. Logistic regression was used to describe associations between the presence or absence of moderate or severe low back pain experienced on most days with BMI. Analyses were conducted separately for males and females, and controlled for age and depression at baseline. Results: Of 14,155 pain question respondents, 11 % of males (n = 710/6475) and 18 % of females (n = 1391/7680) reported moderate or severe low back pain (total 15 %, n = 2101/14,155). Of those reporting moderate or severe low back pain (n = 2101), 55 % reported taking pain-relieving medication regularly, and 29 % reported that the pain regularly interfered with sleep, 37 % with walking, and 47 % with day to day activities. When age and depression were controlled for, there was a statistically significant (p Conclusion: Moderate or severe low back pain is common, has a significant impact, and is associated with either an overweight or obese BMI among community-dwelling Australians aged ≥70 years

Anticholinergic medication burden and cognitive function in participants of the ASPREE study

STUDY OBJECTIVE: What is the association between anticholinergic burden and specific domains of cognitive function in older adults who are initially without major cognitive impairment? DESIGN: Post-hoc analysis of longitudinal observational data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. PATIENTS: 19,114 participants from Australia and the United States aged 70 years and older (65 years and older for US minorities) were recruited and followed for a median of 4.7 years. At enrollment, participants were free of known cardiovascular disease, major physical disability, or dementia. MEASUREMENTS: Cognitive assessments administered at baseline and biennially at follow-up visits included the Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test– Revised (HVLT-R) delayed recall, Controlled Oral Word Association Test (COWAT), and Symbol Digit Modalities Test (SDMT). Anticholinergic burden was calculated at baseline using the Anticholinergic Cognitive Burden (ACB) scale and grouped as scores of 0 (no burden), 1–2 (low to moderate), or 3+ (high). MAIN RESULTS: Linear mixed effects models were used to assess the relationship between ACB score and cognition over time. After adjusting for sex, age, education, minority status, smoking status, hypertension, diabetes, depression, chronic kidney disease, country, and frailty, participants with a high ACB score had worse performance over time for 3MS (Adjusted [Adj] B=−0.092, P=0.034), HVLT-R delayed recall (Adj B=−0.104, P<0.001), COWAT (Adj B=−0.151, P<0.001), and SDMT (Adj B=−0.129, P=0.026), than participants with an ACB score of 0. A low to moderate ACB score was also associated with worse performance over time for HVLT-R delayed recall (Adj B=−0.037, P=0.007) and COWAT (Adj B=−0.065, P=0.003), compared to those with no ACB. CONCLUSIONS: Anticholinergic burden predicts worse cognitive function over time in initially dementia-free older adults, particularly for executive function (COWAT) and episodic memory (HVLT-R)