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Solid tumours are complex and heterogeneous systems, which exist in a dynamic biophysical microenvironment. Conventional cancer research methods have long relied on two-dimensional (2D) static cultures which neglect the dynamic, three-dimensional (3D) nature of the biophysical tumour microenvironment (TME), especially the role and impact of interstitial fluid flow (IFF). To address this, we undertook a transcriptome-wide analysis of the impact of IFF-like perfusion flow using a spheroid-on-chip microfluidic platform, which allows 3D cancer spheroids to be integrated into extracellular matrices (ECM)-like hydrogels and exposed to continuous perfusion, to mimic IFF in the TME. Importantly, we have performed these studies both in experimental (normoxia) and pathophysiological (hypoxia) oxygen conditions. Our data indicated that gene expression was altered by flow when compared to static conditions, and for the first time showed that these gene expression patterns differed in different oxygen tensions, reflecting a differential role of spheroid perfusion in IFF-like flow in tumour-relevant hypoxic conditions in the biophysical TME. We were also able to identify factors primarily linked with IFF-like conditions which are linked with prognostic value in cancer patients and therefore could correspond to a potential novel biomarker of IFF in cancer. This study therefore highlights the need to consider relevant oxygen conditions when studying the impact of flow in cancer biology, as well as demonstrating the potential of microfluidic models of flow to identify IFF-relevant tumour biomarkers. [ABSTRACT FROM AUTHOR]

Background/Aim: Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We, herein, aimed to implement oxygenenhanced MRI (OE-MRI) in xenografts derived from muscleinvasive bladder cancer (MIBC) for future hypoxia biomarker discovery work; and generate gene expression data for future biomarker discovery. Materials and Methods: The flanks of female CD-1 nude mice inoculated with HT1376 MIBC cells. Mice with small (300 mm³) or large (700 mm3) tumours were imaged, breathing air then 100% O2, 1 h post injection with pimonidazole in an Agilant 7T 16cm bore magnet interfaced to a Bruker Avance III console with a T2-TurboRARE sequence using a dynamic MPRAGE acquisition. Dynamic Spoiled Gradient Recalled Echo images were acquired for 5 min, with 0.1mmol/kg Gd-DOTA (Dotarem, Guerbet, UK) injected after 60 s (1 ml/min). Voxel size and field of view of dynamic contrast enhanced (DCE)-MRI and OE-MRI scans were matched. The voxels considered as perfused with significant post-contrast enhancement (p<0.05) in DCE-MRI scans and tissue were further split into pOxyE (normoxic) and pOxyR (hypoxic) regions. Tumours harvested in liquid N2, sectioned, RNA was extracted and transcriptomes analysed using Clariom S microarrays. Results: Imaged hypoxic regions were greater in the larger versus smaller tumour. Expression of known hypoxia-inducible genes and a 24 gene bladder cancer hypoxia score were higher in pimonidazole-high versus -low regions: CA9 (p=0.012) and SLC2A1 (p=0.012) demonstrating expected transcriptomic behaviour. Conclusion: OE-MRI was successfully implemented in MIBC-derived xenografts. Transcriptomic data derived from hypoxic and non-hypoxic xenograft regions will be useful for future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: There are currently limited means by which radiotherapy treatment can be tailored to individual patient needs based on their tumour biology. Published studies of biomarkers aiming to predict tumour sensitivity to radiotherapy treatment for the clinic were reviewed. No gene expression signature biomarkers of sensitivity to radiotherapy are in routine clinical use, have been tested in advanced trials or are recommended for use in clinical guidelines. A pathway for future biomarker development that would enable tools for personalised clinical decision-making is proposed. This focusses on the need to improve the biological understanding of variation in sensitivity to radiotherapy, develop cost-effective assays and conduct large radiotherapy randomised controlled trials. Modern advanced radiotherapy techniques have improved the precision and accuracy of radiotherapy delivery, with resulting plans being highly personalised based on individual anatomy. Adaptation for individual tumour biology remains elusive. There is an unmet need for biomarkers of intrinsic radiosensitivity that can predict tumour response to radiation to facilitate individualised decision-making, dosing and treatment planning. Over the last few decades, the use of high throughput molecular biology technologies has led to an explosion of newly discovered cancer biomarkers. Gene expression signatures are now used routinely in clinic to aid decision-making regarding adjuvant systemic therapy. They have great potential as radiotherapy biomarkers. A previous systematic review published in 2015 reported only five studies of signatures evaluated for their ability to predict radiotherapy benefits in clinical cohorts. This updated systematic review encompasses the expanded number of studies reported in the last decade. An additional 27 studies were identified. In total, 22 distinct signatures were recognised (5 pre-2015, 17 post-2015). Seventeen signatures were 'radiosensitivity' signatures and five were breast cancer prognostic signatures aiming to identify patients at an increased risk of local recurrence and therefore were more likely to benefit from adjuvant radiation. Most signatures (15/22) had not progressed beyond the discovery phase of development, with no suitable validated clinical-grade assay for application. Very few signatures (4/17 'radiosensitivity' signatures) had undergone any laboratory-based biological validation of their ability to predict tumour radiosensitivity. No signatures have been assessed prospectively in a phase III biomarker-led trial to date and none are recommended for routine use in clinical guidelines. A phase III prospective evaluation is ongoing for two breast cancer prognostic signatures. The most promising radiosensitivity signature remains the radiosensitivity index (RSI), which is used to calculate a genomic adjusted radiation dose (GARD). There is an ongoing phase II prospective biomarker-led study of RSI/GARD in triple negative breast cancer. The results of these trials are eagerly anticipated over the coming years. Future work in this area should focus on (1) robust biological validation; (2) building biobanks alongside large radiotherapy randomised controlled trials with dose variance (to demonstrate an interaction between radiosensitivity signature and dose); (3) a validation of clinical-grade cost-effective assays that are deliverable within current healthcare infrastructure; and (4) an integration with biomarkers of other determinants of radiation response. [ABSTRACT FROM AUTHOR]

Hypoxia and a suppressive tumour microenvironment (TME) are both independent negative prognostic factors for muscle-invasive bladder cancer (MIBC) that contribute to treatment resistance. Hypoxia has been shown to induce an immune suppressive TME by recruiting myeloid cells that inhibit anti-tumour T cell responses. Recent transcriptomic analyses show hypoxia increases suppressive and anti-tumour immune signalling and infiltrates in bladder cancer. This study sought to investigate the relationship between hypoxia-inducible factor (HIF)-1 and -2, hypoxia, and immune signalling and infiltrates in MIBC. ChIP-seq was performed to identify HIF1α, HIF2α, and HIF1β binding in the genome of the MIBC cell line T24 cultured in 1% and 0.1% oxygen for 24 h. Microarray data from four MIBC cell lines (T24, J82, UMUC3, and HT1376) cultured under 1%, 0.2%, and 0.1% oxygen for 24 h were used. Differences in the immune contexture between high- and low-hypoxia tumours were investigated using in silico analyses of two bladder cancer cohorts (BCON and TCGA) filtered to only include MIBC cases. GO and GSEA were used with the R packages "limma" and "fgsea". Immune deconvolution was performed using ImSig and TIMER algorithms. RStudio was used for all analyses. Under hypoxia, HIF1α and HIF2α bound to ~11.5–13.5% and ~4.5–7.5% of immune-related genes, respectively (1–0.1% O2). HIF1α and HIF2α both bound to genes associated with T cell activation and differentiation signalling pathways. HIF1α and HIF2α had distinct roles in immune-related signalling. HIF1 was associated with interferon production specifically, whilst HIF2 was associated with generic cytokine signalling as well as humoral and toll-like receptor immune responses. Neutrophil and myeloid cell signalling was enriched under hypoxia, alongside hallmark pathways associated with Tregs and macrophages. High-hypoxia MIBC tumours had increased expression of both suppressive and anti-tumour immune gene signatures and were associated with increased immune infiltrates. Overall, hypoxia is associated with increased inflammation for both suppressive and anti-tumour-related immune signalling and immune infiltrates, as seen in vitro and in situ using MIBC patient tumours. [ABSTRACT FROM AUTHOR]

Learning principles based on brain research include the following: the brain is a parallel processor; learning engages the entire physiology; the search for meaning is innate; emotions are critical to patterning; the brain perceives parts and wholes simultaneously; learning involves focused attention and peripheral perception; and learning is enhanced by challenge, inhibited by threat. (SK)

We examined the effect of two levels of exercise-induced hypotension on esophageal ([T.sub.es]) and active and nonactive muscle temperatures during and following exercise. Seven males performed an incremental isotonic test on a KinCom isokinetic apparatus to determine their peak oxygen consumption during bilateral knee extensions (V[O.sub.2sp]). This was followed on separate days by 15-rain of isolated bilateral knee extensions at moderate (60% V[O.sub.2sp]) (MEI) and high (80% V[O.sub.2sp]) (HEI) exercise intensities, followed by 90 min of recovery. Muscle temperature was measured with an intramuscular probe inserted in the left vastus medialis ([T.sub.vm]) and triceps brachii ([T.sub.tb]) muscles under ultrasound guidance. The deepest sensor (tip) was located ~10 mm from the femur and deep femoral artery and from the superior ulnar collateral artery and humerus for the [T.sub.vm] and [T.sub.tb], respectively. Additional sensors were located 15 and 30 mm from the tip with an additional sensor located at 45 mm for the [T.sub.vm] measurements only. Following exercise, mean arterial pressure (MAP) remained significantly below preexercise rest for the initial 60 min of recovery after MEI and for the duration of the postexercise recovery period after HEI (P [less than or equal to] 0.05). After HEI, significantly greater elevations from preexercise rest were recorded for [T.sub.es] and all muscle temperatures paralleled a greater decrease in MAP compared with MEI (all P [less than or equal to] 0.05). By the end of 90-rain postexercise recovery, MAP, [T.sub.es], and all muscle temperatures remained significantly greater after HEI than MEI. Furthermore, a significantly shallower muscle temperature profile across [T.sub.vm], relative to preexercise rest, was observed at the end of exercise for both HEI and MEI (P [less than or equal to] 0.05), and for 30 rain of recovery for MEI and throughout 90 rain of recovery for HEI. No significant differences in muscle temperature profile were observed for [T.sub.tb]. Thus we conclude that the increase in the postexercise hypotensive response, induced by exercise of increasing intensity, was paralleled by an increase in the magnitude and recovery time of the postexercise esophageal and active muscle temperatures. heat load; thermoregulation; hyperthermia; heat content; and heat balance doi:10.1152/ajpregu.00918.2005.

A study compares the clinical performance of the Canadian Computed Tomography (CT) Head Rule (CCHR) and the New Orleans Criteria (NOC) for detecting the need for neurosurgical intervention and clinically important brain injury. Results show that for patients with minor head injury and a Glasgow Coma Scale (GCS) score of 15, both decision rules have equivalent high sensitivities, but the CCHR has higher specificity for important outcomes and its use may result in reduced imaging rates.

The Canadian C-Spine Rule (CCR) is more accurate than the National Emergency X-Radiography Utilization Study (NEXUS) Low-Risk Criteria for identifying trauma patients who probably do not have an injured neck and therefore do not need a neck X-ray. This was the conclusion of a study of 8,283 patients. The CCR only missed one patient with a neck injury whereas the NEXUS criteria missed 16 patients with a neck injury. The CCR also reduced the number of neck X-rays that were done.

The article examines some moral and ethical concerns arising from animal welfare. Particular focus is given to concerns arising from animal husbandry practices pertaining to life conditions and ending the life of farmed animals. The concepts of new welfarism and illfare reduction are discussed. The four Levels of Harmful Discrimination in the treatment of farmed animals suggested by author David Styzbel are detailed. The focus of animal welfare regulation and legislation on economic interests is tackled.

In order to study the acclimatization process over 14 days of exposure to tropical climate, 9 triathletes performed 4 outdoor indirect continuous multistage tests in both thermoneutral and tropical conditions. The thermoneutral test (TN, 14 °C, 45% th) was performed before traveling to the tropical area (Martinique, FWI). The tropical tests were performed 2, 8, and 14 days after arrival (32.9 °C, 78% rh). During each trial, we measured tympanic temperature, sweat rate, body mass loss, heart rate (HR), and performance. The results showed that 1) the mean tympanic temperature was greater in T2 (P < .001), T8 (P < .01) and T14 (P < .01) than in TN and significantly lower in T14 than in T2 (P < .05); 2) the mean sweat rate was significantly greater (P < .001) in T2, T8 and T14 than in TN and significantly greater (P < .05) in T8 and T14 than in T2; 3) the body mass loss after trials was significantly greater (P < .001) in T2, T8 and T14 than in TN and significantly greater (P < .05) in T8 and T14 than in T2; 4) the mean HR and HR at rest were significantly higher (P < .005) in T2 than in TN, T8, T14 and the mean HR was significantly lower (P < .05) in T14 than in the other trials; and 5) the performance time was significantly lower in T2 (P < 0.02), T8 (P < 0.03) and T14 (P < 0.05) than in TN. We concluded that 14 days of exposure to tropical climate led to changes in physiological parameters but were still insufficient to ensure complete acclimatization in well-trained athletes. The hot/wet climate induced impairment of physiological responses and performance that were still evident on the 14th day. [ABSTRACT FROM AUTHOR]

A technique for implanting multi sensor temperature probes in muscle tissue was developed to optimize the accuracy of the tissue temperature measurements and the internal localization of the probe. Real time ultra-sound imaging was used to (a) determine the best perpendicular insertion tract, (b) guide the insertion of the probe in order to avoid major blood vessels, and (c) verify the insertion point relative to discernable anatomic reference structures such as arteries and bone. [ABSTRACT FROM AUTHOR]

Clinical prediction rules are decision-making tools that incorporate three or more variables from the history, physical examination or simple tests. They help clinicians make diagnostic or therapeutic decisions by standardizing the collection and interpretation of clinical data. There is growing interest in the methodological standards for their development and validation. This article describes the methods used to derive the Canadian C-Spine Rule and provides a valuable reference for investigators planning to develop future clinical prediction rules. [ABSTRACT FROM AUTHOR]

Provides information on the human brain and how the brain works. Discoveries made by neuro-science and cognitive psychology; List of researchers who made significant contributions in understanding the functions of the brain; Proposal of triune brain theory; Details on the nine brain-compatible learning principles.