Adult brain tumour research in 2024: Status, challenges and recommendations

In 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro-oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross-cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom

Corticosterone alters materno-fetal glucose partitioning and insulin signalling in pregnant mice.

Glucocorticoids affect glucose metabolism in adults and fetuses, although their effects on materno-fetal glucose partitioning remain unknown. The present study measured maternal hepatic glucose handling and placental glucose transport together with insulin signalling in these tissues in mice drinking corticosterone either from day (D) 11 to D16 or D14 to D19 of pregnancy (term = D21). On the final day of administration, corticosterone-treated mice were hyperinsulinaemic (P 0.05). Insulin receptor and insulin-like growth factor type I receptor abundance did not differ with treatment in either tissue. Corticosterone upregulated the stress-inducible mechanistic target of rapamycin (mTOR) suppressor, Redd1, in liver (D16 and D19) and placenta (D19), in ad libitum fed animals (P < 0.05). Concomitantly, hepatic protein content and placental weight were reduced on D19 (P < 0.05), in association with altered abundance and/or phosphorylation of signalling proteins downstream of mTOR. Taken together, the data indicate that maternal glucocorticoid excess reduces fetal growth partially by altering placental glucose transport and mTOR signalling.The studies described in this manuscript were supported by a graduate studentship to ORV from the Centre for Trophoblast Research in Cambridge.This is the accepted manuscript of a paper published in The Journal of Physiology Volume 593, Issue 5, pages 1307–1321, 1 March 2015, DOI: 10.1113/jphysiol.2014.28717

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

A transcriptional reference map of defence hormone responses in potato

Phytohormones are involved in diverse aspects of plant life including the regulation of plant growth, development and reproduction, as well as governing biotic and abiotic stress responses. We have generated a comprehensive transcriptional reference map of the early potato responses to exogenous application of the defence hormones abscisic acid, brassinolides (applied as epibrassinolide), ethylene (applied as the ethylene precursor aminocyclopropanecarboxylic acid), salicylic acid and jasmonic acid (applied as methyl jasmonate). Of the 39000 predicted genes on the microarray, a total of 2677 and 2473 genes were significantly differentially expressed at 1 h and 6 h after hormone treatment, respectively. Specific marker genes newly identified for the early hormone responses in potato include: a homeodomain 20 transcription factor (DMG400000248) for abscisic acid; a SAUR gene (DMG400016561) induced in epibrassinolide treated plants; an osmotin gene (DMG400003057) specifically enhanced by aminocyclopropanecarboxylic acid; a gene weakly similar to AtWRKY40 (DMG402007388) that was induced by salicylic acid; and a jasmonate ZIM-domain protein 1 (DMG400002930) which was specifically activated by methyl jasmonate. An online database has been set up to query the expression patterns of potato genes represented on the microarray that can also incorporate future microarray or RNAseq-based expression studies

Dissociable Effects of Valence and Arousal in Adaptive Executive Control

Background: Based on introspectionist, semantic, and psychophysiological experimental frameworks, it has long been assumed that all affective states derive from two independent basic dimensions, valence and arousal. However, until now, no study has investigated whether valence and arousal are also dissociable at the level of affect-related changes in cognitive processing.Methodology/Principal Findings: We examined how changes in both valence (negative vs. positive) and arousal (low vs. high) influence performance in tasks requiring executive control because recent research indicates that two dissociable cognitive components are involved in the regulation of task performance: amount of current control (i.e., strength of filtering goal-irrelevant signals) and control adaptation (i.e., strength of maintaining current goals over time). Using a visual pop-out distractor task, we found that control is exclusively modulated by arousal because interference by goal-irrelevant signals was largest in high arousal states, independently of valence. By contrast, control adaptation is exclusively modulated by valence because the increase in control after trials in which goal-irrelevant signals were present was largest in negative states, independent of arousal. A Monte Carlo simulation revealed that differential effects of two experimental factors on control and control adaptation can be dissociated if there is no correlation between empirical interference and conflict-driven modulation of interference, which was the case in the present data. Consequently, the observed effects of valence and arousal on adaptive executive control are indeed dissociable. Conclusions/Significance: These findings indicate that affective influences on cognitive processes can be driven by independent effects of variations in valence and arousal, which may resolve several heterogeneous findings observed in previous studies on affect-cognition interactions

A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier

BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases

Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer's Disease

Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration

Association of body temperature with obesity. The CoLaus study.

There is conflicting evidence regarding the association between body temperature and obesity. We aimed to assess the associations between body temperature and several adiposity and metabolic markers according to gender and menopausal status in a large population-based sample. The data collected between 2009 and 2012 from 4224 participants (mean age 57.3 ± 10.4 years, 2225 women) of the CoLaus study (Lausanne, Switzerland). Body temperature was measured at the tympanic membrane. Mean body temperature was 36.1 ± 0.4, 36.4 ± 0.4 and 36.3 ± 0.4 °C in men, premenopausal, and postmenopausal women, respectively (p &lt; 0.001). In men and postmenopausal women, body temperature was positively and significantly (p &lt; 0.05) associated with body mass index (Spearman correlation coefficients 0.157 and 0.083, respectively), waist (r = 0.163 and r = 0.104), waist to hip ratio (r = 0.187 and r = 0.132), body area (r = 0.094 and r = 0.085), resting heart rate (r = 0.227 and r = 182), glucose (r = 0.104 and r = 0.088) and insulin (r = 0.148 and r = 0.117). Except for body area and BMI in postmenopausal women, all associations remained significant after multivariable adjustment. In premenopausal women, body temperature was positively associated with resting heart rate (r = 0.140) and insulin (r = 0.170), and no significant associations were found after multivariable adjustment. Body temperature is strongly associated with obesity markers in men and postmenopausal women. The absence of association in premenopausal women might be due to the influence of the menstrual cycle

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery