NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Quantifying health workers’ retention in primary care, its variability and association with outcomes
Funder: The Health Foundation

Abstract: There is an ongoing crisis in the recruitment of GPs, and similar workforce concerns have been raised around general practice nurses. Recent promises of more GPs and medical graduates will not be enough to cover the emerging shortfall.

In light of recruitment problems, it is becoming increasingly important to retain existing practitioners. However, reports have raised concerns about retention trends, and Brexit may also have an impact, with primary care in England relying heavily on overseas-qualified GPs and nurses.

Improving retention rates will improve quality of care for patients and continuity of care, which is associated with better health outcomes and higher levels of patient satisfaction. However, very little is currently known about how retention rates have changed over time and how rates vary across the country.

This project aims to close the retention research gap using databases of routinely collected administrative data. It will examine retention for two key primary care professions: GPs and nurses.

Through this research, the project team aims to provide a blueprint of the use of existing databases in investigating retention and examine the quality of existing data. Metrics of retention will be defined and predictors of retention identified, including quantifying the role of external factors.

Retention levels and trends will be quantified, nationally and regionally, and the team will examine the association between retention and future patient outcomes. Regions and practices with characteristics that make them particularly vulnerable to retention problems will also be identified. All of this information will help policy-makers and primary care managers begin to address retention problems.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Quantifying inequalities in cancer care and cancer outcomes in the UK
Funder: Cancer Research UK

Abstract: Background: There is growing concern that there is significant variation in the quality of cancer care and outcomes across the UK. Although the NHS seeks to ensure that everyone receives the best treatment available and attains the best outcomes possible, significant variation between patient groups persists. The first steps to tackling such inequities are quantifying their size, investigating why they arise and understanding what impact they have on patient outcomes. Data are key to enabling this but, at present, there is a lack of clarity on what information is available and/or required. This application brings together an experienced team from across the UK to respond to the call to address this challenge.

Aim: To map, and help improve, the data landscape relating to cancer inequalities.

Methods: A wide ranging and representative team of academics, data custodians, patient and public representatives and other stakeholders will collaborate to deliver this aim through four parallel work streams (WS).  WS1 will deliver a rapid scoping review of the existing evidence base on cancer inequalities in the UK across the whole care pathway from social determinants to survivorship. WS2 will map the current landscape relating to policy and data initiatives in this area.  WS3 will record and describe all the existing data assets that could be deployed to quantify cancer inequalities as well as identify any important gaps.  If opportunities exist to rapidly fill gaps using existing data then this WS will produce new metrics initially using prostate, breast and bowel cancer as exemplars (but including additional cancers of unmet need if time and resource allows).  WS4 will combine the resulting evidence into a report of findings and then, through discussion with key stakeholders, generate a set of recommendations that will help deliver the evidence required to eliminate cancer inequalities and drive improvements in outcomes across the NHS.

What value will the programme of work deliver: The programme of work will provide a more robust quantification of cancer inequalities within the NHS and an evidence-based series of recommendations that will help address cancer inequalities across the UK.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: CANCER AND NEOPLASMS
Award Title: Quantitative investigation of the control of mRNA degradation in Drosophila early embryogenesis and the impact of stability on developmental processes
Funder: Wellcome Trust

Abstract: Gene expression allows organisms to convert the genetic code in their DNA into proteins which carry out specialised functions in cells. In early embryonic development, cells tailor their gene expression programme to make specific sets of proteins which allow them to transform into a particular type of cell, for example, a skin cell or a neuron. Gene expression has multiple stages including how the process begins, the tuning and travel of RNA molecules along their journey, their conversion into protein as well as the mechanisms by which the cell disposes of them. My work focuses on these degradation mechanisms. We will use large datasets and computational methods including machine learning to estimate degradation rates across different genes throughout embryonic development in the fruitfly model organism and understand the mechanisms controlling these. Our findings will be validated using cutting-edge methods for imaging mRNAs. We will then use other experimental biology techniques including CRISPR-Cas9 genome engineering to change degradation rates of individual mRNAs and examine the effects on cell fates and developmental processes. This will provide us with a greater understanding of how gene expression is controlled, which has implications for many human diseases including cancer, and applications to regenerative medicine.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: R-loop coupled chromatin regulation
Funder: Wellcome Trust

Abstract: Non-canonical chromatin structures are emerging as important components of gene regulation. One example, RNA-DNA hybrid structures known as R-loops, occur frequently in many genomes. Initially studied with respect to genome instability, they have now been linked to transcriptional regulation, heterochromatin formation and recombination. But exactly what regulates R-loop dynamics, and how R-loops influence local chromatin states to affect a wide range of chromatin processes is still poorly understood. Deriving mechanistic understanding of R-loops from genome wide analyses is difficult. We will therefore focus on one functionally important R-loop and exploit a genetically tractable system and a wealth of information to develop deep mechanistic understanding into the regulation and role of an R-loop. We will identify novel factors that stabilize and resolve the R-loop, and establish how their functions are integrated. We will investigate whether the R-loop sets up a transcription-replication conflict that propagates heterochromatinization of the locus, thus setting the expression state. We will also dissect if R-loop dynamics and a gene loop influence promoter dominance to co-ordinate sense and antisense transcription. Active collaborations will enable a broad set of approaches to be used and concepts to be compared between organisms.

Lay Abstract: DNA predominantly exists as a double helix, but increasingly, alternative structures are being found in our genomes. One of these is called an R-loop, and is formed when the messenger molecule made from DNA – a molecule called RNA – loops back and invades the DNA double helix. The pairing between DNA and RNA is very strong, so R-loops can be stable and form ‘hairballs’ in the genome. This prevent normal processes occurring - the DNA cannot be copied and more RNA cannot be made. Until recently, these R-loops were viewed as ‘problems’, but now have also been found to help specific genomic processes. To improve our understanding of these structures we will focus on a particular R-loop that is easy to study, and identify what it does and how it is regulated. This will provide important information on the broader role of these structures in genome regulation generally.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: RElapse-specific therapeutic Vulnerability Evaluation in childhood & young adult ALL (REVEALL) (co-funded by Children with Cancer UK)
Funder: Cancer Research UK

Abstract: Background
Although knowledge of the driver mutations underlying relapsed and refractory paediatric and young adult acute lymphoblastic leukaemia (ALL) has vastly increased in recent years, outcome remains poor. Potential agents targeting many key oncogenic pathways already exist but the relative rarity of relapsed ALL, combined with the wide genetic diversity, makes the testing of targeted therapy using conventional clinical trial design challenging. Children with incurable disease are therefore potentially missing out on effective treatments due to a lack of information to guide therapy.

Aims
To address this, we propose the establishment of a nationwide prospective precision oncology study performing real-time comprehensive analysis of primary leukaemia samples combing genetic characterisation with drug sensitivity profiling. Results will guide delivery of targeted agents directly to the patient and drive a deeper understanding of the cellular underpinnings of relapsed ALL.

Methods
Genomic characterisation will combine whole genome, RNA and ATAC sequencing to identify oncogenic coding variants and aberrant pathways enriched in relapsed and refractory cases. Application of novel in-house bioinformatic pipelines, that integrate sequencing modalities, will allow identification of drivers outside the coding genome, enhancing knowledge of non-coding variants and offering additional potential therapeutic targets, a strategy hitherto unemployed in precision medicine studies.

To extend the availability of novel therapies to patients without a genomic target, drug response profiling utilising an in vitro mesenchymal stem cell-based assay to assess sensitivity in primary leukaemic blasts to a panel of targeted agents. A complementary strategy will employ a novel phosphoproteomic characterisation to identify aberrant pathway activation not apparent on genetic testing. Screening results will be combined with genetic characterisation to provide a powerful resource to identify subtype-specific vulnerabilities that can provide predictive biomarkers for treatment allocation.

Finally, we will develop a library of patient-derived xenograft (PDX) models to facilitate in vivo validation of our results and provide a vital resource for further study of underlying resistance mechanisms.

How the results of this research will be used

We believe our approach will provide direct benefit to children with otherwise untreatable ALL. In addition, the wealth of data will provide a key resource for interrogation of relapsed and refractory ALL, deciphering key mechanisms driving resistance, identifying predictive biomarkers for treatment selection and uncovering new targets for drug development.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: RFID to enable ATMP Manufacturing, Cryogenic Supply Chain Scale-Up and Productivity Gains
Funder: Innovate UK

Abstract: "Manufacture of cell and gene therapies (also known as Advanced Therapy Medicinal Products or ATMPs) is highly labour intensive and technically complex requiring a three-phase process: Primary Manufacturing (production), Secondary Manufacturing (storage, packing and distribution) and Final Preparation (delivery and patient administration), which due to the specialist requirements are currently undertaken by different organisations, using different processes, in separate and often geographically remote locations. The manual processes and multiple handling required to produce ATMPs results in low throughput and high costs.



RFID technology is a well-established technology platform in high-volume sectors, such as the automotive industry and Fast Moving Consumer Goods, and is used to facilitate tracking and traceability of individual components, sub-systems and final product within and between sites. However, these systems cannot be simply transferred across to the ATMP industry due to the unique challenges associated with ATMP manufacture, including aspects of product viability, shelf life, batch sizes, cryogenic temperatures required for product storage and complex regulations to ensure patient safety.



This project will develop and demonstrate a full-scale, regulatory compliant, cryogenic RFID system which works across the three stages of ATMP manufacture. The final system will de-risk and overcome a number of critical barriers to enable full and seamless adoption into the ATMP industry."


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: RNaseH2 inactivation in cancer cells: a pathogenic mechanism and therapeutic target
Funder: Cancer Research UK

Abstract: Background
Cancer cells with defective DNA damage response (DDR) rely on compensatory pathways for their survival. Pharmacological inhibition of these can induce tumour-specific cytotoxicity. We have recently discovered that the DDR gene, RNASEH2B, encoding a subunit of the heterotrimeric enzymatic complex RNaseH2, is frequently deleted in chronic lymphocytic leukaemia (CLL), multiple myeloma (MM) and metastatic prostate cancer. A principal function of RNaseH2 is to enable ribonucleotide excision repair, a DDR pathway that removes ribonucleotides incorporated into DNA by error-prone DNA polymerases. In the absence of RNaseH2 activity, tumour cells rely on PARP and become sensitive to PARP-trapping inhibitors. The full spectrum of phenotypic consequences of RNaseH2 inactivation in tumour cells is unclear, including which pathways become essential for their survival.
Aims
Here we begin to unravel the RNaseH2-associated cancer phenotype and identify cellular vulnerabilities of deficient tumours that can be utilised for therapeutic targeting. Specifically, we aim to:
1.	Use primary CLL as a model to determine the phenotypic consequences of RNaseH2 defects.
2.	Identify other cancers in which RNAseH2 defects can be targeted.
3.	Elucidate key redundancy pathways in RNAseH2-deficient cancer cells by candidate and non-biased approaches.
Methods
We will use an integrated multi-disciplinary approach involving fundamental studies in engineered cell lines, primary tumour cells with defined RNAseH2 status and translational models of CLL and other RNAseH2-deficient cancers. Initially, we will address how RNaseH2-deficiency effects the genomic landscape, tumour burden and inflammation-associated immune evasion by combining our in vitro and in vivo CLL models with cutting-edge genomic analyses and our large patient cohort. Subsequently, we will investigate whether this phenotype exists in other frequent RNAseH2-deficient tumours, such as MM and prostate cancer. Finally, we will use both candidate and non-biased, genome wide approaches to identify the key therapeutic targets in RNaseH2-deficient tumour cells alongside state-of-the-art tumour models to validate their therapeutic utility.
How the results of this research will be used
Our findings have the potential to provide significant benefit for CLL and MM which, with 3000 deaths every year in the UK, clearly represents an unmet need in haemato-oncology, whilst age and patients’ fragility makes a strong case for the use of novel treatments that can replace chemotherapy. Beyond haematological malignancies, the benefits of our studies will be seen in the wider community of Oncology, with respect to prostate cancer, the most common male cancer and the third most common cause of cancer death in the UK.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: RadPath: a pathology network to investigate the immune effects of radiotherapy
Funder: Cancer Research UK

Abstract: Background: Immuno-oncology (IO) agents are revolutionizing the treatment of cancer, but the underlying mechanisms that are responsible for success or failure, including when combining immune checkpoint blockade with radiotherapy (RT), remain poorly understood.  Hence, whilst some clinical success has been seen with RT/IO combinations, the biology of the immune response to RT in patients, in standard of care RT treatments as well as in the context of RT/IO trial combinations, needs in depth investigation to inform future clinical direction and trial strategy.  An under-investigated area of immune analysis of patient samples is pathology, despite the potential of new developments in digitalisation, AI and multicolour immunofluorescence (mIF) to quantify different immune cell subsets.  Pathological readouts of the tumour immune microenvironment (TIME), how it changes with RT, and how it links to other analyses (eg genomic), as well as clinical outcome, can improve both our basic scientific understanding of the immunology of RT, and hence the design of trials to improve patient outcomes.  This proposal has developed from the RadNet Immunology Working Group and focuses on providing immune pathology support across the RadNet network.
Aims: We will establish a co-ordinated immune pathology network (RadPath) across RadNet, led by the Institute of Cancer Research, Manchester and Leeds, with the active participation and support from all other centres.  This infrastructure will allow samples collected from patients taking part in academic or industry-sponsored trials including RT as a treatment modality, to be analysed for their TIME and, where available, normal tissue.  The focus will be on fixed tissue to maximise deliverability, efficiency and affordability.  
Methods: RadPath will first establish shared standard operating procedures, material transfer agreements and data sharing platforms, building on published collaborative work between RadNet centres.  Prioritising initially available samples and those expected within 2 years from ongoing studies, going forward RadPath will also regularly invite potential project proposals.  By requiring further academic and/or industrial funding beyond initial set-up, RadPath will develop longer-term sustainability.
How the results of this research will be used: The results generated by RadPath will be shared across the network.  This will build a network of translational immune pathology science to inform better understanding of the interactions between RT and the immune system, and hence better design of treatment strategies including RT, to improve patient outcome.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health Categories: CANCER AND NEOPLASMS
Award Title: Re-awakening radiation sensitivity - Understanding the role of Schlafen11 in mediating radioresistance.
Funder: Cancer Research UK

Abstract: Background:
Radiotherapy is used in the management of almost 50% of all cancer patients. Therefore, understanding why resistance to radiotherapy occurs is essential for radiotherapy to be used most effectively. Whilst detailed mechanisms of radioresistance remain largely unknown, previous analyses have identified DNA damage response (DDR) pathway alterations correlating with radioresistant phenotypes.

Schlafen11 is an emerging DDR protein whose expression is lost in almost 50% of cancers and cancer cell lines, primarily through promoter methylation. Mechanistic studies have identified Schlafen11 as a key regulator of response to multiple widely used DNA damaging agents (DDA), including potent radiosensitisers, with loss of Schlafen11 expression resulting in broad resistance to these DDA.

Additionally, a number of retrospective studies have demonstrated that Schlafen11 expression loss is a prognostic and predictive biomarker to response to DDA, including chemoradiotherapy combinations. Despite these promising results in multiple cancer types, little is known about the role of Schlafen11 as a mediator of radioresistance.

Aims:
Our aim is to understand the role of Schlafen11 in modulating radioresistance, as well as develop strategies to reverse this resistance.

Methods:
Schlafen11, p53 and dual Schlafen11/p53 isogenic cell lines have previously been generated in our lab through CRISPR-CAS9 knock out in eHAP parental cells. Response to radiation will be compared in these isogenic pairs to identify differential sensitivity related to Schlafen11 and p53 expression. Comprehensive analysis of DNA repair, cell cycle and cell death will be performed to gain a detailed mechanistic understanding of these interactions. Additionally,  ATR, WEE1 and CHK1 inhibitors will be tested in combination with radiation in these cell lines to investigate if these agents can reverse the Schlafen11 resistance as previously demonstrated in the literature.

Further, a whole genome CRISPR knock out screen will be performed in parallel to provide identification of mechanisms of resistance, as well as providing suggestions to how this resistance can be overcome.

How the results of this research will be used:
The information generated, and skills developed, through this proposal will provide preliminary data for a PhD fellowship proposal aiming to optimise the use of radiotherapy by understanding and modulating the DDR. Additionally, these experiments will expand our understanding of Schlafen11 biology to include its role in predicting sensitivity to radiotherapy.


Research Activity Codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Real-world treatment effectiveness in people with type 2 diabetes: Maximising the applicability of clinical trials
Funder: Medical Research Council

Abstract: Randomised controlled trials are the gold standard for obtaining unbiased estimates of treatment effects. However, older patients and those with co-morbidity are frequently underrepresented. Consequently, for many "real-world" settings, the applicability of trial findings is uncertain. We propose to address this uncertainty using calibration. Following calibration trial participants who are overrepresented (with respect to the 'target' population) contribute less to the overall result, while participants who are underrepresented contribute more. Calibration improves representativeness, while preserving randomisation and hence validity. Hitherto, calibration required individual-level participant data (IPD) for all relevant trials, making it unfeasible in most settings. However, in an MRC-funded methodology grant we developed and validated a novel method of calibration, which can be used even where access to IPD is restricted to a subset of the relevant trials. Together with our recent experience in accessing and analysing IPD for industry-funded trials, this makes calibration a feasible tool for improving trial applicability. NICE guidance on novel drugs for type 2 diabetes (DPP-4 and SGLT2-inhibitors and GLP-1 agonists) noted that the underpinning trial evidence was unrepresentative. Therefore, using IPD, sub-group results, and overall results with baseline characteristics, we will conduct a calibrated network meta-analysis of relevant trials to compare the efficacy of these drug classes, subsequently applying these estimates to an existing health economic model. We will calibrate to the Scotland-wide Diabetes Register, and to two cohorts of people with diabetes based in China. We will produce estimates for people with type 2 diabetes that are both valid and applicable. We will also demonstrate, for the first time, that calibration can be used to improve the relevance of trial results in realistic settings, where IPD is only available for some trials.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: METABOLIC AND ENDOCRINE