NIHRDataInsights/HRCSData huggingface dataset:
Title: Can vitamin D protect the airways from inflammation due to particulate matter air pollution that would otherwise drive asthma?
Funder: Wellcome Trust

Abstract: Insufficiency of vitamin D (the sunlight vitamin ) and particulate matter air pollution, for example from diesel engines, are likely major contributors to ill health in asthma (and other diseases). We believe particulate matter pollution contributes to asthma by irritating the airways, driving inappropriate immune responses, and that vitamin D will reduce these harmful effects. We will test these effects on cells in the laboratory using vitamin D treatments and real pollutant extracts from Lo ndon Low Emission Zone monitoring stations. Our early experiments show particulate matter causes airway lining cells to release inflammatory molecules and that this can be reduced by addition of vitamin D. We will investigate how this affects immune cells as asthma is characterised by abnormal immune cell function. We will study the genes regulated by pollution and vitamin D in human lung cells to better understand their effects. The significance of this research is that correction of vita min D levels with supplements may be a safe, easy way to reduce the harmful effects of air pollution on the lungs in asthma and other lung diseases.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RESPIRATORY
Title: Emergency care re-attendance for acute childhood asthma in a low-resource setting: The Childhood Asthma Re-attendance Assessment (CARA) Study
Funder: Wellcome Trust

Abstract: Asthma is a chronic disease that affects the lungs causing difficulty breathing. It is the most common chronic disease worldwide. It is especially common in Latin America, an area where the number of affected children is rising. Asthma attacks are episodes of marked worsening of respiratory symptoms They cause a great deal of suffering and anxiety in patients, permanently damage lung function in the long-term, and can lead to premature death. These attacksmay be prevented with appropriate treatment and lifestyle modifications, such as regularly taking medication or reducing exposure to tobacco smoke. However,there is currently no available tool to identify children at a greater risk ofsuffering these attacks. We intend to follow-up a group of children treated at an emergency department for an asthma attack in Esmeraldas, a city in Ecuador. We will investigate which patient characteristics and tests results are associated with an increased risk of suffering another asthma attack in the following 6 months. These factors will be combined into a tool to identify children at a greater risk of suffering asthma attacks requiring emergency care. Then, this tool will be discussed with a group of asthmatic children and their carers, together with health-care workers to assess the best methods of conveying thisinformation


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY
Title: Collagen assembly and accumulation in idiopathic pulmonary fibrosis.
Funder: Wellcome Trust

Abstract: Idiopathic pulmonary fibrosis (IPF) is a disease of the lungs where abnormal tissue scarring results in loss of the normal lung architecture causing impaired oxygen transfer that ultimately leads to lung failure and death. Worldwide over 5 million people have IPF. There are no effective treatments, and most patients die within 3 years - a prognosis worse than for many types of cancer. It is therefore important to increase our understanding of why IPF develops and to identify effective treatment s. Recent work suggests that increased stiffening of the fibrous lattice surrounding scar forming cells may contribute to their abnormal behaviour; however it is not known how the physical properties of the lattice in IPF lungs are altered. By examining scar tissue from patients with and without IPF I intend to identify differences in lattice stiffness and to determine whether these differences explain why scarring in IPF progresses more rapidly than in other lung diseases. I will then inve stigate how fibroblasts - the lung cells responsible for forming the scar tissue - produce and assemble the lattice within scar tissue. The ultimate goal of this project is to identify targets for therapies to prevent progressive scarring and thus improve patient survival.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Integrin-associated proteins in ventilator-associated lung injury.
Funder: Wellcome Trust

Abstract: The acute respiratory distress syndrome (ARDS) is a process by which the lungs progressively fail, and can follow severe infections or pneumonia. Approximately 40% of patients who develop the syndrome do not survive. A major contributor to ARDS is that artificial ventilation of lungs can make the injury worse, and even cause other organs to fail. The processes by which artificial ventilation causes injury are not clear, and there are no therapies available that can reduce it. My previous work sh ows that when lung cells are stretched, a protein, CD98, helps to convert the mechanical force into harmful chemical signals. I now hope to uncover the precise role this protein has in lung injury following ventilation, and the signaling pathways in human lung cells by which it works. I will test the ability of an agent that blocks the activity of the CD98hc protein to prevent injury in a new model that allows us to study intact human lungs that we can keep alive outside the body for several hou rs. The results of our work will help to establish whether this protein could be targeted by medicines to treat patients who require artificial ventilation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Role of hypoxia in driving local and systemic neutrophil-mediated inflammation in chronic obstructive pulmonary disease (COPD)
Funder: Wellcome Trust

Abstract: In COPD (lung damage due to smoking, including emphysema) white blood cells called neutrophils move from the circulation into the walls of the lung breathing tubes (airways). When stimulated, neutrophils release granules which contain toxic proteins called proteases. Proteases help to kill bacteria but can also damage the delicate structures of the airways and surrounding lung tissue. We have found that low oxygen levels (which occur in patients with COPD) make neutrophils release more toxic pro teins, which damage lung cells. Patients with COPD suffer also from more heart problems than expected, and some patients develop high blood pressure in their lungs which makes them very breathless and reduces their life expectancy. We have found that neutrophils that experience low oxygen destroy a protein called BMP-9, which normally protects the blood vessels in the circulation and in the lung. I want to study how low oxygen levels cause neutrophils to damage the cells that make up blood ves sels, and identify the damaging proteins released by these oxygen-starved neutrophils. I also want to see whether neutrophils have destroyed the BMP-9 that should be protecting the lung circulation in patients with COPD, and if so which specific neutrophil protein is responsible.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The characterisation and treatment of cough in lung cancer: a logitudinal survey and feasibility trial
Funder: Department of Health (England)

Abstract: Cough is under-researched. It represents a significant cause of morbidity and distress in lung cancer patients and their carers. Treatments are inadequate. Progress has been hindered by the lack of suitable assessment tools. A longitudinal survey will be conducted to determine the incidence, frequency, severity and impact of cough in lung cancer as well as factors that correlate with cough. A small cohort within the survey will undergo ambulatory cough monitoring. A feasibility trial will then be conducted in preparation for a phase III trial, comparing methadone linctus and simple linctus for the treatment of cough. This research will improve cough treatment and patient quality of life by better defining cough and providing some evidence base for its treatment.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: Structural studies on human Angiotensin-I converting enzyme (ACE) and the design of novel domain specific inhibitors
Funder: Medical Research Council

Abstract: Somatic angiotensin-I converting enzyme (ACE) - well known for its role in cardiovascular pathophysiology has an unusual, two-domain, double active-site structure. The two domains (designated N and C) are ~55% identical and each contains a similar active site with overlapping but distinct substrate preferences. While both convert angiotensin I to angiotensin II in vitro, current evidence suggests the C domain site predominates in this role in vivo. The N domain site inactivates a hemoregulatory and antifibrotic peptide, AcSDKP, in vivo. However, differences in the characteristics of the two domains may result in different context-dependent activities, as is the case with other enzymes containing tandem repeats. The N domain may also have a role in modulating C domain activity, through a combination of inter-domain cooperativity and structural stabilisation. Recent work on ACE active-site mutants containing one or more key residues replaced by their cognate residues from the other domain, synthesis of domain-selective inhibitors, and co-crystal structures of each domain with such inhibitors, has led to a better insight of the basis for domain selectivity and should enable the design of next-generation, domain-selective inhibitors with distinct pharmacological profiles. In addition, a recent report on the inactivation of the N-terminal catalytic site of ACE significantly reduces bleomycin-induced lung fibrosis and implicates AcSDKP in the mechanism of protection. This work makes a compelling case for the use of N-selective ACE inhibitors for increasing tolerance to bleomycin in cancer therapy and treatment of fibrosing lung diseases. In parallel, the proposed research would also help in better understanding the relationship between the structure and function of somatic ACE.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: Investigating the acute and chronic effects of E-cigarettes on human lungs, examining functional and mechanistic outcomes.
Funder: Wellcome Trust

Abstract: E-cigarettes vaporise nicotine-containing fluid for inhalation and have become an increasingly popular alternative to tobacco. The effects of e-cigarettes on the human lung are incompletely characterised. Preliminary evidence indicates that healthy vapers and smokers have similarly protease rich lung environments. This supports evidence from our lab, demonstrating that e-cigarette exposed alveolar macrophages(AM) increase protease output. I aim to understand the effects of e-cigarettes on the cells of the human lung. Lung resection tissue from never smokers/vapers/smokers/ex-smokers will be used to source AM and type-II alveolar cells, as well as precision cut lung slices (PCLS). Effects will be assessed using techniques to assess viability, proinflammatory mediator production/ROS/protease output, wound repair, phagocytosis and efferocytosis. Simple monocultures/co-cultures will provide initial evidence of e-cigarette effects, whilst PCLS and PCLS/AM cultures will allow effects to be examined in the context of the complex cellular architecture of the lung. In addition, I aim to identify the mechanism(s) of action through which these effects are mediated. Candidate mechanisms will first be tested in co-culture models before validation using our human PCLS model. These studies will help characterise how and why e-cigarettes affect the lungs. This may help inform regulatory decisions and mitigate risks associated with e-cigarette use.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: Pilot feasibility randomised trial of a novel non-pharmacological intervention for the management of the respiratory distress symptom cluster (breathlessness, cough, fatigue) in patients with advanced lung cancer
Funder: Marie Curie

Abstract: Background Our previous work has shown the existence of a complex respiratory distress symptom cluster in patients with lung cancer (breathlessness, cough, fatigue). We have developed a non-pharmacological intervention in an effort to manage better this symptom cluster following the MRC Framework for Complex Interventions. Accordingly, we have published 3 systematic reviews identifying the current state of evidence; we conducted interviews with 37 lung cancer patients and 22 informal caregivers exploring which interventions were more appropriate to use and what would make an intervention more successful; we sought the views of health professionals (through focus groups), and we explored preferences of intervention delivery (n= 88). Aim The aim of this study is to move to the next stage of the MRC Framework and test the feasibility of delivering the intervention in real practice. Methods This will be a feasibility randomised trial using two arms, one receiving best supportive care (standardised for all centres involved) and the other receiving our intervention, focusing both on patients and their carers. The intervention 'package' we have developed through patient and caregiver input will be delivered over two hourly sessions one week apart and will be followed up by a phone call 2 weeks after the face-to-face sessions. It will be delivered after the end of first line treatments close to the patients' home by a specialist nurse with the involvement of caregivers. A number of psychometrically valid scales will be used not only to measure outcomes but also to identify which scales are more sensitive to change and appropriate for use in a full scale trial. Assessments will be taken before randomisation, 4 weeks (end of follow up) and 12 weeks. 100 patients will be recruited from four centres in the North West of England (larger number than usual to accommodate for a 50% attrition due to death or high morbidity). How the results of this study will be used This study will provide initial evidence of the intervention and its delivery methods, and will refine the intervention further. The results of this project will lead to testing the intervention in a large population (phase III trial). If successful, the results will influence the provision of care for patients with lung cancer experiencing complex respiratory symptoms, an area that currently we do not manage well in clinical practice and it has a real potential of improving the patients' and caregivers' quality of life.


Research activity codes: 7.2 END OF LIFE CARE;6.7 PHYSICAL
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: SOX2 and squamous lung cancer
Funder: Wellcome Trust

Abstract: In the UK, squamous lung cancer (SQC) accounts for 40% of lung cancer cases. It has a massive impact on society, and the survival figures are unchanged over the last few decades. Apart from smoking cessation, the best way to improve outcomes is to develop a better understanding of the nature, sequence and impact of the key molecular events that cause the disease, and use this information to inform treatment and prevention strategies. This proposal is focused on understanding the role of S OX2, a potential driving gene, in SQC. I will have three objectives. The first is to understand the timing of SOX2 dysregulation, and potential synergistic genetic events, in the earliest stages of cancer development. The second is to build a model of early SQC, incorporating results from the first objective. The final objective is to build the first valid mouse model of SQC, focusing on the role of SOX2 and potentially synergistic genes. This project can transform our understanding of the mo lecular causes of SQC. It has the potential to develop models that will enhance this understanding, and allow the rational preclinical testing of current and novel drugs. This may have a directl positive impact on patient outcomes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: Defining the role of Lrig1- dependent EGFR signalling pathway inhibition in airway homeostasis and lung cancer development.
Funder: Wellcome Trust

Abstract: Lung cancer is the commonest cause of UK cancer death, yet how lung cancer develops remains poorly understood. Molecular signalling through a pathway called the EGFR pathway causes cell growth, new blood vessel formation and repair from injury. This signalling can become overactivated in lung cancer, causing cancer formation. Our bodies contain molecules that block overactivation of this pathway, one of which is the molecule Lrig1. Lrig1 is lost in cancers of the skin and gut, this means signalling through the EGFR pathway is unopposed and tumours develop. Dr Janes lab has recently shown its loss in the early stages of lung cancer development. My project looks at Lrig1 in more detail. Interestingly, I have shown Lrig1 is present in areas of dividing cells in the developing mouse airway. I aim to establish the function of Lrig1 in normal, developing and repairing lung tissue, and how Lrig1 loss results in lung cancer starting. By understanding the role and function of L rig1 in normal airway development and repair I can then look at ways of reversing loss of Lrig1 in lung cancer and design new therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS
Title: 'Muslim Communities Learning About Second-hand Smoking-MCLASS Study
Funder: Cancer Research UK

Abstract: Smoking prevalence is significantly higher among Pakistani and Bangladeshi communities in the UK compared to the national average. In collaboration with Muslim leaders, we have developed a Smoke-Free Homes manual for mosques to encourage their congregation to implement smoking restrictions at home. We have already established its appropriateness in mosques and its feasibility in respective communities. We propose to conduct a pilot study to answer statistical uncertainties around sample size, recruitment and attrition rates. The study will assess feasibility of measuring the proposed outcomes and allows us to test and improve the trial protocol in advance of a large trial.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: RESPIRATORY;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Smoking prevention in young people: A cluster randomised controlled trial of implementation intentions
Funder: Cancer Research UK

Abstract: This research would test an intervention to reduce smoking initiation in adolescents initially aged 11-12 years over a 4 year time period. The intervention would employ a simple but effective strategy to refuse offers of cigarettes (if-then plans about how to say no to offers of cigarettes) against a control condition. The intervention would be conducted in schools in classroom time on nine occasions. The outcome measure would be smoking behaviour assessed by self-report and more objective measures (smokerlyser) at ages 11-12, 12-13, 13-14, 14-15, and 15-16 years.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: RESPIRATORY;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Effectiveness & cost-effectiveness of mass media campaigns in reducing smoking & smoking-related disease in UK
Funder: Cancer Research UK

Abstract: There is international evidence that anti-smoking mass media campaigns can be effective in changing attitudes and smoking behaviour, but there is still little known of the relative influence of different types of campaign, or of their impact in specific population sub-groups. Moreover, there is very little evidence of the effectiveness, or cost-effectiveness, of campaigns in the UK. The lack of UK evidence has enabled the government to cease funding mass media campaigns, making work in this area an immediate priority. The aim of the proposed research is to evaluate the impact of mass media campaigns in the UK since 2002 and to determine what types of campaign are most effective and cost-effective using a comprehensive set of key indicators of their immediate and longer term impacts, including smokers’ attitudes, knowledge and behaviour, smoking prevalence, smoking in the home, and smoking-related health outcomes. We will use a combination of observational approaches, time series analysis and longitudinal panel study analysis, taking data from existing national datasets including The Health Improvement Network primary care data (smoking prevalence, smoking cessation medication prescriptions, consultations for smoking-related disease), Omnibus survey (prevalence), NHS quitline calls, smoking cessation service attendees and 4 week quitters, Nicotine Replacement Therapy (NRT) sales, Hospital Episode Statistics (heart attacks), and Health Survey for England (children’s cotinine measurements). Monthly aggregates for many of these are available in our Nottingham Tobacco Control Database, developed in previous NPRI-funded work. Time series analysis will be used to statistically model the population-level change in smoking behaviours and health outcomes in relation to specific campaigns, or month-to-month change in their advertising reach and spend, allowing for underlying trends, seasonality, and impacts of other tobacco control policies. Longitudinal analysis will use International Tobacco Control (ITC) survey data; panel studies of over 2000 adult daily smokers and recent ex-smokers, in each of the UK, US, Canada and Australia. ITC data will be used to assess awareness of mass media campaigns, and individual changes in smoking behaviour, knowledge and attitudes pre and post individual UK campaigns. The planned project will be carried out collaboratively between the Universities of Nottingham and Bath, both part of the UK Centre for Tobacco Control Studies, a UK Public Health Research Centre of Excellence. This provides an ideal context within which to carry out this work, and to ensure that our findings are used in driving effective policy development and implementation.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: RESPIRATORY;CANCER AND NEOPLASMS;CARDIOVASCULAR