ReIMAGINE: a prostate cancer research consortium with added value through its patient and public involvement and engagement.

BACKGROUND: ReIMAGINE aims to improve the current prostate specific antigen (PSA)/biopsy risk stratification for prostate cancer (PCa) and develop a new image-based method (with biomarkers) for diagnosing high/low risk PCa in men. ReIMAGINE's varied patient and public involvement (PPI) and engagement (PE) strategy maximises the impact of its scientific output by informing and shaping the different stages of research. AIMS: Through including the voice of patients and the public, the ReIMAGINE Consortium aims to translate these different perspectives into the design and implementation process. This will improve the overall quality of the research by: reflecting the needs and priorities of patients and the public, ensuring methods and procedures are feasible and appropriate ensuring information is relevant and accessible to those being recruited to the study identifying dissemination channels relevant to patients/the public and developing outputs that are accessible to a lay audience With support from our patient/user groups, the ReIMAGINE Consortium aims to improve our ability to derive prognostic information and allocate men to the most appropriate and effective therapies, using a novel image-based risk stratification with investigation of non-imaging biomarkers. FINDINGS: We have been working with patients and the public from initiation of the project to ensure that the research is relevant to men and their families. Our PPI Sub-Committee, led by a PCa patient, has been involved in our dissemination strategy, outreach activities, and study design recommendations. For example, the sub-committee have developed a variety of informative videos relevant and accessible to those being recruited, and organised multiple online research engagement events that are accessible to a lay audience. As quoted by one of the study participants, "the more we present the benefits and opportunities to patients and the public, the more research commitment we obtain, and the sooner critical clinical questions such as PCa diagnostics will be addressed".

One in eight men will be diagnosed with prostate cancer (PCa). Most will not die of it, but our ability to identify those men whose cancer poses the greatest threat to life has, thus far, been poor. Some men are diagnosed with small cancers which will never cause them a problem, some will have treatment which is unnecessary, others will have their cancers missed, and others will be misclassified as either having low risk cancer and will therefore miss out on the appropriate treatment, or told their cancer is high risk and have unnecessary treatment. Nowhere else in modern medicine are these errors of over-diagnosis, over-treatment, missed-diagnoses, and poor risk-stratification more common. The ReIMAGINE Consortium has been developed to undertake discoveries that will correct these four key errors in the PCa diagnostic pathway. We will investigate how to best identify which men have, or will develop, aggressive prostate cancer using imaging combined with advanced biomarker analyses of blood and urine (i.e., OMICs technologies such as whole genome sequencing, targeted sequencing (e.g.: = , methylation). We will achieve this by building on established partnerships between patients, advocacy organisations, clinicians, imaging experts, molecular biologists, methodologists, and a broad range of industrial partners.The Patient and Public Involvement (PPI) sub-committee is an integral part of the study workflow, contributing to study design and recruitment, results analysis, and dissemination. The committee, led by a funded PPI co-ordinator and a patient chair, have given invaluable insight into the study modifications due to COVID-19 restrictions.

Guy's cancer cohort - real world evidence for cancer pathways.

BACKGROUND: The burden of disease due to cancer remains substantial. Since the value of real-world evidence has also been recognised by regulatory agencies, we established a Research Ethics Committee (REC) approved research database for cancer patients (Reference: 18/NW/0297). CONSTRUCTION AND CONTENT: Guy's Cancer Cohort introduces the concept of opt-out consent processes for research in a subset of oncology patients diagnosed and treated at a large NHS Trust in the UK. From April 2016 until March 2017, 1388 eligible patients visited Guy's and St Thomas' NHS Foundation Trust (GSTT) for breast cancer management. For urological cancers this number was 1757 and for lung cancer 677. The Cohort consists of a large repository of routinely collected clinical data recorded both retrospectively and prospectively. The database contains detailed clinical information collected at various timepoints across the treatment pathway inclusive of diagnostic data, and data on disease progression, recurrence and survival. CONCLUSIONS: Guy's Cancer Cohort provides a valuable infrastructure to answer a wide variety of research questions of a clinical, mechanistic, and supportive care nature. Clinical research using this database will result in improved patient safety and experience. Guy's Cancer Cohort promotes collaborative research and will accept applications for the release of anonymised datasets for research purposes.

King's Health Partners' Prostate Cancer Biobank (KHP PCaBB).

The KHP PCaBB was established in 2013 and recruits donors from the Urology or Oncology Departments at Guy's Hospital in London (UK). Prostate cancer patients may be approached to give their consent for biobanking at any point in their treatment pathway, which allows residual material from their earlier diagnosis to be transferred and used by the Biobank. Currently, patients are specifically asked to donate samples of blood and surplus prostate tissue as well as permitting access to their clinical and pathological data that continues to be added throughout the course of their disease. Between 2013 and 2015, 549 prostate cancer patients gave their consent to the biobank and, the tissue repository collected 489 blood samples, 120 frozen prostate tissue samples and 1064 formalin fixed paraffin embedded diagnostic blocks.Prostate cancer has become a chronic disease in a large proportion of men, with many men receiving multiple subsequent treatments, and their treatment trajectory often spanning over decades. Therefore, this resource aims to provide an ideal research platform to explore potential variations in treatment response as well as disease markers in the different risk categories for prostate cancer.A recent audit of the KHP PCaBB revealed that between 2013 and 2015, 1796 patients were diagnosed with prostate cancer at King's Health Partners (KHP), out of which 549 (30.6%) gave their consent to KHP PCaBB. Comparisons between demographic and clinical characteristics of patients who had consented compared to the total patient population revealed that the KHP PCaBB is demographically representative of the total prostate cancer patient population seen in Guy's and St Thomas' NHS Foundation Trust (GSTT). We observed no differences in distribution of ethnicity (p = 0.507) and socioeconomic status (p = 0.097). Some differences were observed in clinical characteristics, specifically with treatment type - which differed significantly between the patients who had given consent and total patient population.The KHP PCaBB has thereby amassed a rich data and tissue repository that is largely reflective of both the demographic and clinical diversity within the total prostate cancer patient population seen at KHP, making it an ideal platform for prostate cancer research.

Real World Evidence: A Quantitative and Qualitative Glance at Participant Feedback from a Free-Response Survey Investigating Experiences of a Structured Exercise Intervention for Men with Prostate Cancer.

AIM: To explore patient experiences of a structured exercise intervention for men with prostate cancer (PCa). SAMPLE: 41 men with either localised or advanced PCa who had been referred for a structured exercise programme by their physician and then subsequently consented to a telephone survey. METHOD: Participants underwent a 10-week supervised exercise programme within a large cancer centre hospital consisting of 8 sessions. They then completed a short multiple choice telephone survey, elaborating on their responses where appropriate. Views expressed by participants were analysed using an affinity diagram and common themes were identified. RESULTS: Feedback from our telephone surveys was consistently positive and suggests that the structured exercise intervention provides exercise confidence, motivation to exercise, and social support and promotes positive health behaviour change in the context of exercise. Individual differences arose amongst participants in their perceived utility of the intervention, with 73.3% expressing a preference for structured exercise classes and 19.5% expressing a preference for exercising independently. CONCLUSION: Design of a structured exercise intervention for patients with PCa should embrace the positive aspects outlined here but consider patients' individual differences. Ongoing feedback from patients should be utilised alongside traditional study designs to inform intervention design in this area.

The effect of lower body cooling on the changes in three core temperature indices.

Rectal (T(re)), ear canal (T(ear)) and esophageal (T(es)) temperatures have been used in the literature as core temperature indices in humans. The aim of the study was to investigate if localized lower body cooling would have a different effect on each of these measurements. We hypothesized that prolonged lower body surface cooling will result in a localized cooling effect for the rectal temperature not reflected in the other core measurement sites. Twelve participants (mean ± SD; 26.8 ± 6.0 years; 82.6 ± 13.9 kg; 179 ± 10 cm, BSA = 2.00 ± 0.21 m(2)) attended one experimental session consisting of sitting on a rubberized raft floor surface suspended in 5 °C water in a thermoneutral air environment (approximately 21.5 ± 0.5 °C). Experimental conditions were (a) a baseline phase during which participants were seated for 15 min in an upright position on an insulated pad (1.408 K ⋅ m(2) ⋅ W(-1)); (b) a cooling phase during which participants were exposed to the cooling surface for 2 h, and (c) an insulation phase during which the baseline condition was repeated for 1 h. Temperature data were collected at 1 Hz, reduced to 1 min averages, and transformed from absolute values to a change in temperature from baseline (15 min average). Metabolic data were collected breath-by-breath and integrated over the same temperature epoch. Within the baseline phase no significant change was found between the three indices of core temperature. By the end of the cooling phase, T(re) was significantly lower (Δ = -1.0 ± 0.4 °C) from baseline values than from T(ear) (Δ = -0.3 ± 0.3 °C) and T(es) (Δ = -0.1 ± 0.3 °C). T(re) continued to decrease during the insulation phase from Δ -1.0 ± 0.4 °C to as low as Δ -1.4 ± 0.5 °C. By the end of the insulation phase T(re) had slightly risen back to Δ -1.3 ± 0.4 °C but remained significantly different from baseline values and from the other two core measures. Metabolic data showed no variation throughout the experiment. In conclusion, the local cooling of the buttock area results in a drop in rectal temperature compromising the validity of the rectal temperature as a core temperature index under these conditions.

Antagonism of nitrous oxide antinociception in mice by intrathecally administered antisera to endogenous opioid peptides.

Previously it was demonstrated that nitrous oxide antinociception in the mouse abdominal constriction test is mediated by kappa-opioid receptors. Since nitrous oxide is thought to cause the neuronal release of endogenous opioid peptide to stimulate opioid receptors, this study was designed to identify the opioid peptides involved, especially in the spinal cord, by determining whether nitrous oxide antinociception can be differentially inhibited by intrathecally (i. t.) administered antisera to different opioid peptides. Male NIH Swiss mice were pretreated i.t. with rabbit antisera to opioid peptides then exposed 24 h later to one of three different concentrations of nitrous oxide in oxygen. Dose-response curves constructed from the data indicated that the antinociceptive effect of nitrous oxide was significantly antagonized by antisera to various dynorphins (DYNs) and methionine-enkephalin (ME), but not by antiserum to beta-endorphin (beta-EP). The AD(50) values for nitrous oxide antinociception were significantly elevated by antisera to DYNs and ME but not beta-EP. These findings of this study support the hypothesis that nitrous oxide antinociception in the mouse abdominal constriction test involves the neuronal release of DYN and ME in the spinal cord.

Role of brain dynorphin in nitrous oxide antinociception in mice.

Earlier studies indicate that nitrous oxide antinociception is mediated by opioid receptors, and we have hypothesized that nitrous oxide stimulates a neuronal release of an endogenous opioid peptide (EOP) that stimulates opioid receptors. To further test this hypothesis, male NIH Swiss mice were pretreated intracerebroventricularly with rabbit antisera to opioid peptides or with various inhibitors of peptidases involved in the degradation of EOPs. Mice were subsequently exposed to three different concentrations of nitrous oxide in oxygen, and their antinociceptive responsiveness was measured using the acetic acid abdominal constriction test. Nitrous oxide antinociception was significantly attenuated by 24-h pretreatment with antisera to various fragments of dynorphin (DYN) but not by antisera against methionine-enkephalin (ME) or beta-endorphin (beta-EP). In other experiments, nitrous oxide antinociception was significantly enhanced by 30-min pretreatment with phosphoramidon, an inhibitor of endopeptidase 24.11, which has been implicated in DYN degradation, but not bestatin or captopril, which inhibit aminopeptidase and angiotensin-converting enzyme, respectively. The latter enzymes have been implicated in degradation of certain EOPs albeit not DYN. These findings support the hypothesis that nitrous oxide antinociception in the mouse abdominal constriction test is mediated by endogenous DYN acting in the central nervous system.

The statolith compartment in Chara rhizoids contains carbohydrate and protein.

In contrast to higher plants, the alga Chara has rhizoids with single membrane-bound compartments that function as statoliths in gravity perception. Previous work has demonstrated that these statoliths contain barium sulfate crystals. In this study, we show that statoliths in Chara rhizoids react with a Coomassie Brilliant Blue cytochemical stain for proteins. While statoliths did not react with silver methenamine carbohydrate cytochemistry, the monoclonal antibody CCRC-M2, which is against a carbohydrate (sycamore-maple rhamnogalacturonan I), labeled the statolith compartment. These results demonstrate that in addition to barium sulfate, statoliths in Chara rhizoids have an organic matrix that consists of protein and carbohydrate moieties. Since the statoliths were silver methenamine negative, the carbohydrate in this compartment could be a 3-linked polysaccharide. CCRC-M2 also labeled Golgi cisternae, Golgi-associated vesicles, apical vesicles, and cell walls in the rhizoids. The specificity of CCRC-M2 immunolabeling was verified by several control experiments, including the demonstration that labeling was abolished when the antibody was preabsorbed with its antigen. Since in this and a previous study (John Z. Kiss and L. Andrew Staehelin, American Journal of Botany 80: 273-282, 1993) antibodies against higher plant carbohydrates crossreacted with cell walls of Chara in a specific manner, Characean algae may be a useful model system in biochemical and molecular studies of cell walls.

Potassium: aldosterone relationships in pregnant ewes and chronically cannulated ovine fetuses.

UNLABELLED: As maternal hyperkalemia quickly induces fetal hyperkalemia, it was decided to investigate the effect of small elevations of plasma [K+] on the peripheral blood aldosterone concentration in chronically catheterized ovine fetuses and to compare this response to that obtained in the adult ewe both pregnant and nonpregnant. Fol elevations of plasma [K+] of 0.1 to 0.3 mmole/liter blood aldosterone concentrations were elevated by 6.7 +/- 4.9 (9) ng/dl in nonpregnant sheep, 6.3 +/- 5.0 (6) in pregnant ewes, but only 0.3 +/- 1.7 (4) in fetal sheep. For increments in plasma [K+] of 0.4--1.0 mmole/liter aldosterone increments in nonpregnant ewes were 9.5 +/- 4.5 (4) ng/dl compared with 10.1 +/- 4.7 (5) in pregnant ewes and 1.5 +/- 2.6 (7) in fetuses. There was no obvious correlation between the age of the fetus and the response to increased plasma [K+]. In effect, the blood aldosterone concentration of the fetus was not elevated by increasing plasma plasma [K+]. SPECULATION: The ovine fetus is not able to cope with hyperkalemia by increasing blood aldosterone concentration. Until the fetus is close to term, hyperkalemia may jeopardize the pregnancy by causing placental hemorrhages.

Passive transport of 5,5-dimethyl-2, 4-oxazolidinedione into beef heart mitochondria.

5,5-Dimethyl-2,4-oxazolidinedione is used to estimate intracellular pH. The mechanism of transport of this compound into beef heart mitochondria was investigated to assess the validity of its use for the measurement of intramitochondrial pH. This compound and (14)C-labeled carboxy dextran were simultaneously used to determine the intra- and extramitochondrial compartments and the distribution of the compound, which was passively transported into resting, respiring, and simultaneously respiring and phosphorylating mitochondria. The transport of the compound was neither associated with electron transport nor with oxidative phosphorylation.