Traveling waves in a coarse-grained model of volume-filling cell invasion: Simulations and comparisons

Many reaction–diffusion models produce traveling wave solutions that can be interpreted as waves of invasion in biological scenarios such as wound healing or tumor growth. These partial differential equation models have since been adapted to describe the interactions between cells and extracellular matrix (ECM), using a variety of different underlying assumptions. In this work, we derive a system of reaction–diffusion equations, with cross-species density-dependent diffusion, by coarse-graining an agent-based, volume-filling model of cell invasion into ECM. We study the resulting traveling wave solutions both numerically and analytically across various parameter regimes. Subsequently, we perform a systematic comparison between the behaviors observed in this model and those predicted by simpler models in the literature that do not take into account volume-filling effects in the same way. Our study justifies the use of some of these simpler, more analytically tractable models in reproducing the qualitative properties of the solutions in some parameter regimes, but it also reveals some interesting properties arising from the introduction of cell and ECM volume-filling effects, where standard model simplifications might not be appropriate

The Foot Orthoses versus Hip eXercises (FOHX) trial for patellofemoral pain:a protocol for a randomized clinical trial to determine if foot mobility is associated with better outcomes from foot orthoses

Background: Patellofemoral pain (PFP) is a prevalent, often recalcitrant and multifactorial knee pain condition. One method to optimize treatment outcome is to tailor treatments to the patient's presenting characteristics. Foot orthoses and hip exercises are two such treatments for PFP with proven efficacy yet target different ends of the lower limb with different proposed mechanisms of effect. These treatments have not been compared head-to-head, so there is a dearth of evidence for which to use clinically. Only foot orthoses have been explored for identifying patient characteristics that might predict a beneficial effect with either of these two treatments. Preliminary evidence suggests patients will do well with foot orthoses if they have a midfoot width in weight bearing that is≥11mm more than in non-weight bearing, but this has yet to be verified in a study that includes a comparator treatment and an adequate sample size. This trial will determine if: (i) hip exercises are more efficacious than foot orthoses, and (ii) greater midfoot width mobility will be associated with success with foot orthoses, when compared to hip exercises. Methods: Two hundred and twenty participants, aged 18-40 years, with a clinical diagnosis of PFP will be randomly allocated with a 1:1 ratio to receive foot orthoses or progressive resisted hip exercises, and stratified into two subgroups based on their presenting midfoot width mobility (high mobility defined as ≥11mm). The primary outcome will be a 7-point Likert scale for global rating of change. All analyses will be conducted on an intention-to-treat basis using regression models. Discussion: This trial is designed to compare the efficacy of foot orthoses versus hip exercise, as well as to determine if high midfoot width mobility is associated with better outcomes with foot orthoses when compared to hip exercises. Results of this trial will assist clinicians in optimising the management of those with PFP by testing whether a simple measure of midfoot width mobility can help to determine which patients are most likely to benefit from foot orthoses. Trial registration: This trial is registered on the Australian New Zealand Clinical Trials Register (ACTRN12614000260628

Modeling the extracellular matrix in cell migration and morphogenesis:a guide for the curious biologist

The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role in many biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Development of a global measure of job embeddedness and integration into a traditional model of voluntary turnover

Recent research on job embeddedness has found that both on- and off-the-job forces can act to bind people to their jobs. The present study extended this line of research by examining how job embeddedness may be integrated into a traditional model of voluntary turnover. This study also developed and tested a global, reflective measure of job embeddedness that overcomes important limitations and serves as a companion to the original composite measure. Results of this longitudinal study found that job embeddedness predicted voluntary turnover beyond job attitudes and core variables from traditional models of turnover. Results also found that job embeddedness interacted with job satisfaction to predict voluntary turnover, suggesting that the job embeddedness construct extends beyond the unfolding model of turnover (T. R. Mitchell & T. W. Lee, 2001) it originated from

Inhibition monitoring in veterinary molecular testing

Many of the sample matrices typically used for veterinary molecular testing contain inhibitory factors that can potentially reduce analytic sensitivity or produce false-negative results by masking the signal produced by the nucleic acid target. Inclusion of internal controls in PCR-based assays is a valuable strategy not only for monitoring for PCR inhibitors, but also for monitoring nucleic acid extraction efficiency, and for identifying technology errors that may interfere with the ability of an assay to detect the intended target. The Laboratory Technology Committee of the American Association of Veterinary Laboratory Diagnosticians reviewed the different types of internal controls related to monitoring inhibition of PCR-based assays, and provides information here to encourage veterinary diagnostic laboratories to incorporate PCR internal control strategies as a routine quality management component of their molecular testing