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.

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.

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 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.

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.

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.

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.

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.

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

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.

Brain barriers and brain fluid research in 2016: advances, challenges and controversies.

This editorial highlights some of the advances that occurred in relation to brain barriers and brain fluid research in 2016. It also aims to raise some of the attendant controversies and challenges in such research.

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery.

Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We used array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor "inflamed" and "non-inflamed" tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic, and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo Cancer Immunol Res; 5(1); 29-41. ©2016 AACR.

How to refer to people with disease in research outputs: The disconnection between academic practise and that preferred by people with multiple sclerosis.

BACKGROUND: Increasingly, Government and Charity funders require public engagement in research. Invariably these research outputs describe the condition of someone with the disease of interest. We therefore sought to identify the preferred descriptor of someone with a disease, such as multiple sclerosis (MS) and to determine what descriptors are currently used by academics. METHODS: Several surveys were undertaken: one from the Research Network of the MS Society (MSSRN), a major MS Charity within the United Kingdom, who are involved in reviewing grant applications, priority setting and research governance (n=146), and surveys from both the United Kingdom MS register (MSR; n=1713) and the North American Research Committee on Multiple Sclerosis (NARCOMS) registry (n=518). People were asked to rate descriptors of someone affected with MS. These were compared to that used by academic experimenters in basic science and clinical science research papers. RESULTS: Although the frequency of responses varied between surveys the overall findings showed many consistencies. This included use of person/people with MS (pwMS) as the preferred descriptor for someone with MS for social media and scientific publications. This was the preferred choice in about 55-60% people from the MRS and in over 70% in the NARCOMS and the MSSRN, respectively. Although MSer was the second preferred-choice for use in social media, there was as a large range of preferences from the 'most-preferred' to the 'most-disliked.' This reflected an earlier survey by UK-based research blogs using the term MSer (n=173). In contrast, pwMS had few 'dislikes' and results were skewed towards the 'liked' and 'most-preferred' choices. Client and sufferer were generally disliked terms, although there was some regional variation in levels of choice. Patient was generally seen as a neutral term that was neither strongly liked nor disliked. However, patient gained more public support for use within scientific publications (~20-25%) compared to social media (~10-15%). This descriptor was however most commonly used (98-99%) within both pre-clinical (searched in 6-month output of preclinical autoimmune MS models; n=161) and in clinical publications (specialist MS journals; n=220), whereas pwMS was not reported in over 75% of papers published in some specialised MS journals, and did not appear in the pre-clinical animal studies examined. CONCLUSION: There is a clear disconnection between preferences by individuals living with MS and current academic practise. As pwMS are increasingly reading primary research publications and are involved in patient and public involvement in research and grant review activities, the sensitivities of lay readers should be considered when writing research outputs. This issue may affect other diseases and a change in writing style could be adopted to show that we respect the wishes of the people that we study and wish to help.

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Advances in brain barriers and brain fluid research and news from Fluids and Barriers of the CNS.

Research into brain barriers and brain fluids has been advancing rapidly in recent years. This editorial aims to highlight some of the advances that have improved our understanding of this complex subject. It also brings you news of developments for Fluids and Barriers of the CNS including a new affiliation between the journal and the International Society for Hydrocephalus and CSF disorders.

Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.

Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.

Physical disability, anxiety and depression in people with MS: an internet-based survey via the UK MS Register.

INTRODUCTION: People with Multiple Sclerosis are known to have a relatively high prevalence of both anxiety and depression. Studies of the relationship between physical disability and mental health in people with MS have reported mixed results, showing the need for further work. METHODS: Between May 2011 and April 2012, 4516 people completed the MSIS-29 (v.1) and HADS scales via the dedicated internet site of the UK MS Register within a 7 day time window. These responses were linked with basic demographic and descriptive data and analysed in SPSS (v.20). RESULTS: The proportions of people experiencing anxiety or depression increased with physical disability such that 38.0% of respondents with low, and 66.7% with high disability reported at least mild anxiety, and 17.1% of people with low, and 71.7% with high disability experienced at least mild depression. The multiple regression model explained 18.4% of the variance in anxiety with MSIS-29-PHYS score being the strongest predictor of anxiety. The model for depression explained 37.8% of the variance with MSIS-29-PHYS score being the strongest predictor. Some of the other variables included showed negative associations with anxiety and depression, indicating that the influence of physical disability on mental wellbeing could be underestimated. CONCLUSIONS: This study indicates that there is a positive relationship between physical disability and anxiety and depression, that physical disability impacts on anxiety and depression to differing extents, and that the effects vary with gender, age, disease course and disease duration. We have shown that physical disability is a predictor of anxiety and depression, and that other factors may mask the extent of this effect. Whether the causes of anxiety and depression are reactive, organic or a combination, it is essential that mental wellbeing is given due attention in caring for people with MS so that all their health needs can be met.