The role of mouse tumour models in the discovery and development of anticancer drugs.

Our understanding of cancer biology has increased substantially over the past 30 years. Despite this, and an increasing pharmaceutical company expenditure on research and development, the approval of novel oncology drugs during the past decade continues to be modest. In addition, the attrition of agents during clinical development remains high. This attrition can be attributed, at least in part, to the clinical development being underpinned by the demonstration of predictable efficacy in experimental models of human tumours. This review will focus on the range of models available for the discovery and development of anticancer drugs, from traditional subcutaneous injection of tumour cell lines to mice genetically engineered to spontaneously give rise to tumours. It will consider the best time to use the models, along with practical applications and shortcomings. Finally, and most importantly, it will describe how these models reflect the underlying cancer biology and how well they predict efficacy in the clinic. Developing a line of sight to the clinic early in a drug discovery project provides clear benefit, as it helps to guide the selection of appropriate preclinical models and facilitates the investigation of relevant biomarkers.

Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models. Few data exist from patients with PAH. METHODS AND RESULTS: Dynamic positron emission tomography imaging with fluorine-18-labeled 2-fluoro-2-deoxyglucose ((18)FDG) ligand with kinetic analysis demonstrated increased mean lung parenchymal uptake in 20 patients with PAH, 18 with idiopathic PAH (IPAH) (FDG score: 3.27±1.22), and 2 patients with connective tissue disease (5.07 and 7.11) compared with controls (2.02±0.71; P<0.05). Further compartment analysis confirmed increased lung glucose metabolism in IPAH. Lung (18)FDG uptake and metabolism varied within the IPAH population and within the lungs of individual patients, consistent with the recognized heterogeneity of vascular pathology in this disease. The monocrotaline rat PAH model also showed increased lung (18)FDG uptake, which was reduced along with improvements in vascular pathology after treatment with dicholoroacetate and 2 tyrosine kinase inhibitors, imatinib and sunitinib. Hyperproliferative pulmonary vascular fibroblasts isolated from IPAH patients exhibited upregulated glycolytic gene expression, along with increased cellular (18)FDG uptake; both were reduced by dicholoroacetate and imatinib. CONCLUSIONS: Some patients with IPAH exhibit increased lung (18)FDG uptake. (18)FDG positron emission tomography imaging is a tool to investigate the molecular pathology of PAH and its response to treatment.

In vivo mapping of vascular inflammation using the translocator protein tracer 18F-FEDAA1106.

Noninvasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F-FEDAA1106 and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG, a marker of glucose metabolism) for positron emission tomographic (PET) imaging of vascular inflammation. This was tested using a murine model in which focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomic data generated by computed tomographic (CT)/CT angiography. Standardized uptake values were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p < .01) or FDG (p < .05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the noninflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 corresponded with vascular inflammation more specifically than FDG uptake.

Role of the subcommissural organ in the pathogenesis of congenital hydrocephalus in the HTx rat.

The present investigation was designed to clarify the role of the subcommissural organ (SCO) in the pathogenesis of hydrocephalus occurring in the HTx rat. The brains of non-affected and hydrocephalic HTx rats from embryonic day 15 (E15) to postnatal day 10 (PN10) were processed for electron microscopy, lectin binding and immunocytochemistry by using a series of antibodies. Cerebrospinal fluid (CSF) samples of non-affected and hydrocephalic HTx rats were collected at PN1, PN7 and PN30 and analysed by one- and two-dimensional electrophoresis, immunoblotting and nanoLC-ESI-MS/MS. A distinct malformation of the SCO is present as early as E15. Since stenosis of the Sylvius aqueduct (SA) occurs at E18 and dilation of the lateral ventricles starts at E19, the malformation of the SCO clearly precedes the onset of hydrocephalus. In the affected rats, the cephalic and caudal thirds of the SCO showed high secretory activity with all methods used, whereas the middle third showed no signs of secretion. At E18, the middle non-secretory third of the SCO progressively fused with the ventral wall of SA, resulting in marked aqueduct stenosis and severe hydrocephalus. The abnormal development of the SCO resulted in the permanent absence of Reissner's fibre (RF) and led to changes in the protein composition of the CSF. Since the SCO is the source of a large mass of sialilated glycoproteins that form the RF and of those that remain CSF-soluble, we hypothesize that the absence of this large mass of negatively charged molecules from the SA domain results in SA stenosis and impairs the bulk flow of CSF through the aqueduct.

Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation.

RATIONALE: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. OBJECTIVE: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. METHODS AND RESULTS: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. CONCLUSIONS: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis.

A year in review: brain barriers and brain fluids research in 2022.

This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

The feasibility of collecting information from people with Multiple Sclerosis for the UK MS Register via a web portal: characterising a cohort of people with MS.

BACKGROUND: A UK Register of people with Multiple Sclerosis has been developed to address the need for an increased knowledge-base about MS. The Register is being populated via: a web-based portal; NHS neurology clinical systems; and administrative data sources. The data are de-identified and linked at the individual level. At the outset, it was not known whether people with MS would wish to participate in the UK MS Register by personally contributing their data to the Register via a web-based system. Therefore, the research aim of this work was to build an internet-mounted recruitment and consenting technology for people with Multiple Sclerosis, and to assess its feasibility as a questionnaire delivery platform to contribute data to the UK MS Register, by determining whether the information provided could be used to describe a cohort of people with MS. METHODS: The web portal was developed using VB.net and JQuery with a Microsoft SQL 2008 database. UK adults with MS can self-register and enter data about themselves by completing validated questionnaires. Descriptive statistics were used to characterise the respondents. RESULTS: The web portal was launched in May 2011, and in first three months 7,279 individuals registered on the portal. The ratio of men to women was 1:2.4 (n = 5,899), the mean self-reported age at first symptoms was 33.8 (SD 10.5) years, and at diagnosis 39.6 (SD 10.3) years (n = 4,401). The reported types of MS were: 15% primary progressive, 63% relapsing-remitting, 8% secondary progressive, and 14% unknown (n = 5,400). These characteristics are similar to those of the prevalent MS population. Employment rates, sickness/disability rates, ethnicity and educational qualifications were compared with the general UK population. Information about the respondents' experience of early symptoms and the process of diagnosis, plus living arrangements are also reported. CONCLUSIONS: These initial findings from the MS Register portal demonstrate the feasibility of collecting data about people with MS via a web platform, and show that sufficient information can be gathered to characterise a cohort of people with MS. The innovative design of the UK MS register, bringing together three disparate sources of data, is creating a rich resource for research into this condition.

Advances in brain barriers and brain fluids research in 2021: great progress in a time of adversity.

This editorial highlights advances in brain barrier and brain fluid research in 2021. It covers research on components of the blood-brain barrier, neurovascular unit and brain fluid systems; how brain barriers and brain fluid systems are impacted by neurological disorders and their role in disease progression; and advances in strategies for treating such disorders.

Brain Barriers and brain fluids research in 2020 and the fluids and barriers of the CNS thematic series on advances in in vitro modeling of the blood-brain barrier and neurovascular unit.

This editorial discusses advances in brain barrier and brain fluid research in 2020. Topics include: the cerebral endothelium and the neurovascular unit; the choroid plexus; the meninges; cerebrospinal fluid and the glymphatic system; disease states impacting the brain barriers and brain fluids; drug delivery to the brain. This editorial also highlights the recently completed Fluids Barriers CNS thematic series entitled, 'Advances in in vitro modeling of the blood-brain barrier and neurovascular unit'. Such in vitro modeling is progressing rapidly.

Mild endotoxemia during mechanical ventilation produces spatially heterogeneous pulmonary neutrophilic inflammation in sheep.

BACKGROUND: There is limited information on the regional inflammatory effects of mechanical ventilation and endotoxemia on the production of acute lung injury. Measurement of F-fluorodeoxyglucose (F-FDG) uptake with positron emission tomography allows for the regional, in vivo and noninvasive, assessment of neutrophilic inflammation. The authors tested whether mild endotoxemia combined with large tidal volume mechanical ventilation bounded by pressures within clinically acceptable limits could yield measurable and anatomically localized neutrophilic inflammation. METHODS: Sheep were mechanically ventilated with plateau pressures = 30-32 cm H2O and positive end-expiratory pressure = 0 for 2 h. Six sheep received intravenous endotoxin (10 ng x kg x min), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused N-nitrogen and F-FDG to compute regional perfusion and F-FDG uptake. Transmission scans were used to assess aeration. RESULTS: Mean gas fraction and perfusion distribution were similar between groups. In contrast, a significant increase in F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the F-FDG uptake was associated with regional aeration (P < 0.01) and perfusion (P < 0.01). CONCLUSIONS: Mild short-term endotoxemia in the presence of heterogeneous lung aeration and mechanical ventilation with pressures within clinically acceptable limits produces marked spatially heterogeneous increases in pulmonary neutrophilic inflammation. The dependence of inflammation on aeration and perfusion suggests a multifactorial basis for that finding. F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions.

This was the year that was: brain barriers and brain fluid research in 2019.

This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

The year in review: progress in brain barriers and brain fluid research in 2018.

This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood-CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.

Hydrocephalus 2008, 17-20th September, Hannover Germany: a conference report.

Hydrocephalus 2008 was held 17-20 September in Hannover, Germany, at the invitation of Petra M Klinge (President), co-hosted by Joachim K. Krauss (Vice President), and Madjid Samii (Honorary President). This meeting was a successor to Hydrocephalus 2006 held in Göteborg, Sweden, organised by Past-President, Carsten Wikkelso. The conference began with a general introductory session of six talks including three invited lectures, followed by eighteen parallel sessions. Subjects covered were hydrocephalus signs, symptoms and diagnosis, especially in normal pressure hydrocephalus; cerebrospinal fluid (CSF) physics and dynamics; CSF function and modelling of function; dementia and quality of life, economy, health care and rehabilitation; neuropsychology, cognition and outcome assessment; neuroimaging, functional imaging and non-invasive diagnostics; paediatric and adolescent hydrocephalus; intelligent shunt and valve design (e.g. telemetry, adjustable and antimicrobial shunts); endoscopic third ventriculostomy; technical advances and image-guided surgical approaches in the treatment of hydrocephalus; brain metabolism, biomarkers and biophysics; co-morbidity, classification and aetiology; epidemiology, registries and clinical trials; experimental hydrocephalus; and pharmaceutical modulation of central nervous system function (CNS drug delivery). Each session began with introductory talks from the invited chairpersons followed by six to eight submitted oral presentations. Overall, 136 oral presentations and 18 posters were presented, the abstracts of which were published elsewhere 1. We present here an account of the introductory session, the invited chairperson's talks and the concluding remarks by Anthony Marmarou.

PET scanning of macrophages in patients with scleroderma fibrosing alveolitis.

RATIONALE: Assessment of disease activity in fibrosing alveolitis due to systemic sclerosis (FASSc) is difficult without using invasive investigation. A repeatable noninvasive method of assessing disease at a cellular level such as with positron emission tomography (PET) could be of great value in evaluating high-resolution changes in the pathological process. OBJECTIVES: To investigate whether the level of inflammatory cell traffic and lung density in FASSc, imaged in vivo by PET, is different to controls and whether they are associated with changes in pulmonary function indices. METHODS: We used PET to measure lung density and tissue uptake of (11)C-[R]-PK11195, a ligand that binds to receptors found in abundance in macrophages. Fifteen patients with FASSc were compared to seven controls. RESULTS: A trend of reduced uptake of (11)C-[R]-PK11195 was observed in FASSc patients (P=.09) and correlated inversely with lung density (r=-.62; P<.05), which was significantly elevated in FASSc [0.35+/-0.02 vs. 0.23+/-0.02 g/cc (mean+/-S.E.M.); P<.005]. CONCLUSION: These results demonstrate that inflammatory cell traffic and lung density can be imaged in vivo in FASSc using PET, and that this approach might be of potential value in understanding, in situ, components of pathogenesis that may have value for prognosis.

Progress in brain barriers and brain fluid research in 2017.

The past year, 2017, has seen many important papers published in the fields covered by Fluids and Barriers of the CNS. This article from the Editors highlights some.

A Cluster-Randomized Trial to Evaluate the Impact of an Inclusive, Community-Led Total Sanitation Intervention on Sanitation Access for People with Disabilities in Malawi.

Community-led total sanitation (CLTS) is a common method for promoting sanitation in low-income settings. This cluster-randomized trial evaluated an intervention to improve inclusion of people with disability in CLTS through training facilitators. A qualitative study examined intervention acceptability. The trial included 171 people with disabilities (78 control and 93 intervention) living in 15 intervention and 15 control communities. In the intervention arm, respondents were more likely to participate in a community meeting about sanitation (+18.7%, 95% confidence interval [CI]: 3.2, 34.2) and to have been visited to discuss sanitation (+19.7, 95% CI: 0.6, 37.8). More intervention households improved latrine access for the disabled member (+9%, CI: -3.1, 21.0). Inclusive CLTS could improve sanitation access for people with disability but requires support to households beyond that provided in this trial.

Correction to: Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.