NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Evaluating the impact of the Mais Médicos (More Doctors) programme in Brazil
Funder: Medical Research Council

Abstract: The Programa Mais Médicos (more doctors programme) (PMM) is a key strategy to expand Brazil's family health strategy in underserved areas. Little robust evidence exists on the impact of interventions to increase human resources for health (HRH) such as the PMM on access to healthcare, health outcomes, and wider health system impacts. The evidence gap is largest in low- and middle-income countries where distributional inequalities in HRH are greatest. Robust impact evaluations of the PMM as an internationally recognised supply-side intervention is vital to inform HRH policy in Brazil and globally. We plan to evaluate the PMM using quantitative and qualitative methods. We will conduct quantitative analysis of all municipalities for national generalizability. For qualitative analyses, we will select 24 municipalities in the Integrated Development Region of the Federal District (RIDE/DF) and the state of Paraiba that have introduced PMM doctors. We will conduct a quasi-experimental evaluation of routinely available data using difference-in-difference methods to assess the impact of the PMM on mortality and morbidity. We will expand these analyses to examine heterogeneity of impact across programmatic factors (e.g. different municipalities and types of doctors) and population characteristics (including age, sex and racial groups) to draw inference on health inequalities. We also plan to evaluate whether PMM uptake across municipalities was in line with Federally-established criteria of need, and what effect expansion in non-priority municipalities may have had on overall impact. We will conduct qualitative research in the form of clinic observation and semi-structured interviews with national implementers, local health managers and PMM doctors to better understand facilitators and barriers to successful implementation, including broader health system constraints and how these were addressed by managers and clinicians.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Exploiting mechanisms of centrosome dysfunction in the treatment of 17q23-amplified breast cancer
Funder: Breast Cancer Now

Abstract: Background
Relapsed and metastatic breast cancer poses high risk to patient survival as resistance to multiple lines of chemotherapy is often observed. Identifying new druggable targets is an imminent need to treat recurrent breast cancer. My group has discovered an aberrant genetic mechanism causing centrosome dysfunction in breast cancer cells that harbour 17q23-amplification, a well-known, recurrent copy number alteration (CNA) found in around 10% of all primary breast tumours that is associated with medium to poor clinical outcomes. We identified a vulnerability linked to this mechanism: a complete reliance on centrosomes for cell division. The defect is linked to the overexpression of TRIM37, an E3 ubiquitin ligase located at 17q22-23 within the amplicon. Importantly, our work showed this defect can be exploited to eliminate cancer cells with 17q23-amplification: treatment with an inhibitor of Polo-like kinase 4 (PLK4), which blocks centriole duplication and leads to centrosome loss, drives cells into catastrophic mitoses resulting in cancer cell death.
 

Aims
We aim to expand our understanding of the mechanisms driving the cytotoxic effect of PLK4 inhibition and the mutations leading to resistance to PLK4 inhibition. We will also identify additional pathways/processes whose targeting synergises with PLK4 inhibition or TRIM37 overexpression to drive cancer cell death. 
 

Techniques and Methodology
Genes whose mutation leads to resistance to PLK4 inhibition will be identified by a genome-wide CRISPR screen and direct targeting of proteins in TRIM37 complex. Additional CRISPR screens will be performed to discover depleted mutants in response to PLK4 inhibition or TRIM37 overexpression. Subsequent validation and characterization of identified targets will involve targeted gene-knockouts, microscopy, biochemical and cell biological approaches.
 

Impact on breast cancer research
This proposal will test and define the therapeutic potential of targeting centrosome dysfunction in 17q23-amplified breast cancer. It will also advance our understanding of this poorly understood breast cancer CNA.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Exploratory development of CB213, a LAG3-PD1 targeting Humabody for a first in human Phase I clinical trial in PD-1 refractory/relapse patients
Funder: Cancer Research UK

Abstract: Combination therapy utilising two or more agents to simultaneously target synergistic pathways is already considered a cornerstone of cancer therapy. The benefits of mAb-based combination therapy is also well known and has been illustrated very clearly by the positive survival impact for advanced melanoma patients who received the combination of ipilimumab plus nivolumab. However, the fact that a substantial proportion of these patients also experienced an increase in treatment-limiting (treatment-related) toxicity proved that simple combinations are not always the answer. It is increasingly clear that in order to lift the tail of the survival curve beyond the effect of mere combinations requires the sort of profound effect that can only be achieved by accessing novel biology through the simultaneous engagement of one or more targets by bi-/multispecific molecules.
 
Crescendo has created a transgenic mouse capable of producing fully human VH domains ('Humabody VH') in response to immunisation. In the absence of any contaminating immunoglobulin light chains, the Humabody VH are imbued with highly robust biophysical characteristics and make excellent building blocks for creating multivalent/multispecific fusion molecules. CB213 is a uniquely formated tetravalent Humabody molecule capable of optimally engaging and antagonising both PD1 and LAG3.

CB213 is uniquely designed to drive dual-checkpoint blockade solely in those highly exhausted T cells co-expressing both targets in a way that simply combining monospecific monoclonal antibodies against each individual target (or indeed any 'standard bispecific format) is unable to achieve. CB213 uniquely not only drives enhanced proliferation and activation in the most dysfunctional TILs but also avoids the peripheral sink of PD1-single positive T-cells with the view to delivering an improved safety profile over other competing bispecifics. In combination with its small size (~60kDal) and the use of a serum albumin binding domain for half-life extension, CB213 has optimal PK characteristics for driving deeply into and accumulating in tumours thereby enhancing its ability to access the TME. 

CB213 is a first in class molecule optimally formatted for delivery of safe, effective therapeutic benefit in a patient population with high unmet need and Crescendo would welcome the opportunity to work with CRUK to explore the development of CB213 in a first-in-human clinical trial of relapse/refractory PD-1 patients.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Exploring combination therapy to optimise costimulation blockade in autoimmunity
Funder: Diabetes UK

Abstract: Costimulation blockade is a widely used strategy to dampen T cell responses in the setting of autoimmunity. It slowed beta-cell destruction when trialled in individuals with new onset type 1 diabetes (T1D), however benefits were deemed insufficient to support routine use of this therapy.  One drawback of inhibiting CD28 costimulation is that this same pathway is also needed to support regulatory T cell (Treg) homeostasis.  Thus, at the same time as inhibiting pathogenic T cells, the treatment also reduces Treg numbers.  This undesirable side-effect impairs natural immunosuppression.  We have found that this limitation can be offset by combining costimulation blockade with low dose IL-2 therapy.  The resulting combination therapy supports Treg homeostasis while retaining inhibition of pathogenic T cell responses.  Preliminary data suggest this combination therapy is highly effective at inhibiting diabetes in a mouse model.  We now wish to follow up these exciting findings to understand key mechanistic questions about this therapy and its potential utility.  Are the Treg that are rescued in this manner equivalent to normal Treg in their phenotype and suppressive properties? Is the therapy still effective if administered after diabetes has developed? Our findings could lead to a new approach for therapeutic intervention in T1D.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES;5.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Exploring innate-like and adaptive gamma delta T cell paradigms in health and disease
Funder: Wellcome Trust

Abstract: γδ T-cells have been retained in vertebrates for ~500million years, and are of increasing therapeutic interest, but their mode of ligand recognition and immunological niche has remained largely mysterious. Here we build on the emergence of parallel innate-like and adaptive human γδ T-cell paradigms to address unresolved ‘keystone’ questions in γδ T-cell biology. Firstly, we will exploit multidisciplinary approaches to explore the diversity of innate-like and adaptive γδ biology in different tissues, their coordination with other immune responses, and how these change in disease states such as inflammation and cancer. Secondly, we will identify molecular targets of γδ-TCRs from innate-like subsets and structurally characterise their TCR/ligand interactions and cellular/molecular recognition mechanisms, focussing significantly on the strong emergence of Butyrophilin family molecules as critical TCR-ligands for such populations. Thirdly we will exploit cytomegalovirus infection as a unique human model to identify novel ligands for antigen-experienced adaptive-like γδ T-cell subsets. Finally, we will develop and apply new methodology to image and phenotype distinct human γδ T-cell subsets in solid tissues, using multispectral immunofluorescence and digital spatial profiling. This programme should help revolutionise our understanding of γδ T-cells, and provide a solid foundation for ongoing efforts to therapeutically harness the γδ T-cell compartment.

Lay Abstract: Background to the research problem
 
Our research is focussed on an unusual type of immune cell called ‘gamma-delta T-cells’. These are evolutionarily ancient and powerful, capable of recognising and killing infected or cancerous cells. However, it has remained unclear how gamma-delta cells recognise signs of abnormality on target cells, and in which immune scenarios this occurs.
 
Our approach
 
Our research plan combines different techniques to explore two key subtypes of gamma-delta T cells, and determine the molecular targets they recognise on infected or cancerous cells. We will also assess how they function in different tissues of the body, and how their function changes during disease states.
 
Expected impact
 
The research should revolutionise our understanding of a very important and poorly understood type of immune cell, and will pave the way for scientists to exploit them in new therapies against infection and cancer.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Exploring the Links Between Regulatory T cell Populations and Development of HLA Antibodies in Renal Patients Awaiting Transplantation.
Funder: Medical Research Council

Abstract: Immunologically sensitised patients account for approximately 50% of the renal transplant waiting list and have circulating antibodies (Ab) against different HLA. Getting a suitable donor kidney for those with a very broad array of HLA Ab can be difficult, because of the risk of immediate Ab-mediated rejection, so they wait a long time, and more of them die whilst waiting. Once transplanted, these patients suffer higher rates of rejection and shortened graft lives, consequent on activation of immune memory responses. Relatively little is understood about why some patients become sensitised whilst others don't, nor why different routes of sensitisation associate with different relative risks. My project is to investigate the hypothesis that sensitisation arises in some patients but not others due to variation in the ability of patients own regulatory T cells (Tregs) to suppress interactions between alloreactive T and B cells. Building on established techniques, I will first document the number and phenotype of Treg subsets in patients with failing transplants or pregnant renal patients, the two main routes of sensitisation. I will then look at the functional differences between patients' Tregs using two suppressor assays, including one to suppress B cell production of Ab. Then, using fluorospot assays to assess anti-HLA interferon gamma and IL-17 production, I will compare the suppressive capacity of Tregs from patients sensitised by pregnancy to those sensitised by a failing transplant. Finally, I will explore the variation in Treg protease activated receptor (PAR) expression and whether manipulating signalling through surface PAR-4 can enhance Treg suppressive ability. I will also test whether cathepsin K is a natural Treg ligand for PAR-4. All this work will inform whether future therapeutic interventions based on boosting patients Treg numbers or suppressive capacity can prevent HLA sensitisation and improve the wellbeing of patients awaiting a kidney transplan


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Exploring the implications of new and novel alternative nicotine products in superdiverse areas for health inequalities
Funder: Cancer Research UK

Abstract: Background  While inequalities in nicotine/tobacco use have largely been explored from the perspective of socio-economic status (SES) or class, there has been little focus to date on the ways in which multiple aspects of population diversity – including SES, age, gender, race/ethnicity, nationality, religion and immigration status  – intersect differentially to shape the use of nicotine/tobacco products. The availability and use of increasingly diverse nicotine/tobacco products – such as e-cigarettes and shisha – has also created new questions about the implications for health inequities. Therefore, this project will use a place-based approach to focus on the increasing demographic complexity of populations in urban areas and the ways in which nicotine/tobacco use and provision is becoming more diverse. Moving beyond monolithic approaches to diversity which focus on singular aspects of diversity and assume ‘within group’ homogeneity, this research will instead adopt a ‘superdiversity’ approach. It will consider the multiple and intersecting differences associated with diverse populations within a particular neighbourhood and how these relate to nicotine/tobacco use. Given these newer products are likely to vary significantly in their relative harm, differences in understandings, perceptions and experiences of use in a superdiverse area must be explored to identify the health inequalities likely to emerge, and the implications for the adaptability, acceptability and intensity of smoking cessation interventions.    Research Aim  This project will explore understandings, perceptions and experiences of use of diverse nicotine/tobacco products among people in a superdiverse area of the UK (Handsworth, Birmingham), to identify potential health inequalities and approaches for facilitating a switch by individuals to less harmful products.     Methods  A qualitative research design will be co-produced in conjunction with the local community. Ethnographic mapping of the study area will identify the availability and consumption of different nicotine/tobacco products. Semi-structured interviews with adults from the area will explore ‘rules of access’ to these features. A maximum variation sampling strategy will be developed to reflect the diverse make-up of Handsworth residents. Providers of nicotine/tobacco products will also be interviewed to investigate the variable uptake and demand for particular types of nicotine/tobacco products.    Results  The findings and analysis will be disseminated through the researchers’ existing networks and will include ‘key findings’ papers for policy-makers and also academic papers for high impact, peer-reviewed journals.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: CANCER AND NEOPLASMS
Award Title: Exploring the role of glypicans in modulating morphogen signalling and stem cell dynamics
Funder: Wellcome Trust

Abstract: Wnt and Hedgehog signalling regulate intestinal stem cell dynamics to ensure intestinal renewal, function and integrity is maintained. The activation of these two pathways involves crosstalk and communication between the mesenchymal and epithelial layers of the intestine. However, a puzzling conundrum is that both Wnt and Hedgehog carry hydrophobic lipid moieties that are required for receptor binding and signalling but that also hinder their solubility and diffusion and hence ability to move between intestinal cells. In Drosophila, the glypican Dally-like protein (Dlp), which possess a lipid binding pocket, binds and shields the lipid moiety of Wnts to aid transport. Dlp is also essential for initiating Hedgehog signalling but its precise mechanism of action is unknown. I will determine if Dlp also binds the lipid moieties of Hedgehog and what such binding means for Hedgehog solubility, transport and receptor engagement. I will determine if mammalian homologues of Dlp also bind the lipid moieties of Wnt and Hedgehog to regulate their activity and whether they are required in the mouse intestine for Wnt and Hedgehog signalling to orchestrate stem cell dynamics. A deep understanding of how glypicans modulate Wnt and Hedgehog signalling will answer major questions in developmental and stem cell biology.

Lay Abstract: In order to build and maintain complex tissues cells communicate with each other to coordinate their actions. They do so by sending signalling molecules to each other. A breakdown in communication leads to abnormal development and disease states, including intestinal cancers. Hence it is vital to understand how signals are packaged, transported and recognized by cells.

Using molecular biology and Drosophila genetics I will elucidate how glypican proteins facilitate the spread of signalling molecules between cells and their recognition on intended recipient cells. Then by altering glypican expression in the mouse intestine, I will investigate what role glypicans play in sending and receiving signals in vivo in the mammalian intestine and if they are needed for intestinal regeneration and health. A thorough understanding of glypican function in cell-to-cell communication is expected to facilitate the design of therapeutic interventions to treat diseases such as intestinal cancers that arise from aberrant signalling.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Award Title: FAB - Targeting cell senescence to treat chronic wounds
Funder: Innovate UK

Abstract: This project aims to develop a novel approach to healing chronic wounds, a major societal health concern in the elderly and in diabetics. For most healthy people, a cut or scrape heals rapidly on its own, but in diabetics and the elderly wounds can fail to heal, remaining open, needing treatment and causing suffering for months. Five Alarm Bio (FAB) is developing drugs that help the body defend against the chemical damage of aging, damage that is one of the reasons that chronic wounds fail to heal. This project will aim to prove the concept that FAB can use those drugs as a treatment for chronic wounds. FAB will test these new drugs for their ability to keep skin cells healthy for longer, and for their ability to help those cells close up artificial 'wounds' in cell culture in the lab. Success in the project will allow FAB to take the best drugs forward, ultimately to testing them on real patients.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INJURIES AND ACCIDENTS;METABOLIC AND ENDOCRINE
Award Title: Factors predicting the transition from acute to persistent pain in people with 'sciatica' - the FORECAST study
Funder: Medical Research Council

Abstract: Sciatica is a common condition (43% lifetime prevalence) and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared to low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. Unfortunately, it remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (e.g., symptom severity, routine magnetic resonance imaging, depression) are consistent prognostic factors. Given the failure of traditional variables as prognostic factors, a novel approach is required to understand who may develop persistent pain.  FORECAST includes a prospective prognostic cohort study that aims to: 1. Explore mechanism-based subgroups in patients with sciatica, using deep phenotyping. 2. Investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica. We will evaluate prognostic factors for pain persistence in n=180 patients with acute/subacute sciatica. Prognostic variables will be assessed at baseline and outcome at 3 and 12 months. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small datasets will be used to identify the most powerful predictors and model selection/accuracy.  This project is based on our strong feasibility data and has been shaped by in-depth patient involvement. The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and identify prognostic factors of pain persistence. This will ultimately facilitate patient stratification and streamline management pathways to increase quality of life for patients with sciatica.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: NEUROLOGICAL