NIHRDataInsights/HRCSData huggingface dataset:
Title: Over two years to investigate a rational strategy for the management of renal complications in children with sickle cell disease.
Funder: Action Medical Research

Abstract: Background Sickle cell disease is the most common serious genetic condition worldwide. About 300,000 babies with sickle cell disease are born each year worldwide. It is also a significant problem in the UK, where around one baby born in every 1,900 has a sickle cell disease. People with sickle cell disease have an abnormal form of haemoglobin known as HbS in their red blood cells. This causes red blood cells to become crescent or sickle-shaped and they can get stuck in small blood vessels. Complications are first seen during early childhood. Some children show few clinical signs, whilst others are severely affected, experiencing chronic anaemia, pain and organ damage, requiring frequent hospitalisation. Kidney disease occurs in about a third of children with sickle cell disease and significant numbers develop renal (kidney) failure, requiring dialysis or transplantation. Currently, it is not possible to identify the subset of children who will develop kidney disease. Although we do not fully understand how sickle cell disease causes renal problems, it is likely that changes in red blood cell membranes are involved. Sickle cell disease alters the membrane of the red blood cell making the cell more fragile and likely to breakdown which is thought to contribute to the risk of damage to the kidneys. The research project The investigators want to improve their understanding of the relationship between red blood cell abnormalities and kidney complications in children with sickle cell disease. They believe that red blood cell membrane abnormalities contribute significantly to renal damage and importantly, these abnormalities will be detectable before the development of kidney problems They will measure red blood cell membrane permeability in blood samples taken from children with sickle cell disease and see if these measurements correlate with clinical signs of renal damage such as protein in the urine and high blood pressure. It is hoped that this research will provide a method of identifying those children who are at risk of developing renal complications. This would mean that treatments could be started before renal damage occurs, limiting the extent of future kidney disease and improving the quality of life of these children.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;RENAL AND UROGENITAL
Title: Erythropoietin therapy for treating anaemia among haemodialysis patients: associations with survival and comparison of treatment strategies
Funder: Medical Research Council

Abstract: Background: Anaemia is common in people with kidney disease and results in reduced quality of life, including symptoms of fatigue, dizziness, and shortness of breath. Anaemia can be treated by injections of erythropoietin (EPO). However, at present we do not know enough about the safety of high doses of EPO or of full correction of anaemia to normal haemoglobin levels. Aims and objectives: We aim to establish the optimal use of EPO therapy for haemodialysis patients. I will describe haemoglobin levels in patients and EPO dosing over time in the UK, and will compare trends to changes in the national Renal Associations guidelines for management of anaemia. I will describe haemoglobin variability and EPO resistance in individuals. I will quantify the predictors of EPO treatment and examine the effect of EPO dose on mortality. Finally I will compare different treatment strategies to optimise survival and give the lowest risk of hospitalisation. Methods: The UK Renal Registry regularly collects data on adults receiving renal replacement therapy from all centres across the UK, and will provide data on patients receiving haemodialysis. Relevant patient information will be extracted from the database, including: age, sex, disease information, results from blood tests, EPO dose and treatment dates. I will apply marginal structural models to correctly control for time-dependent confounding, and the novel statistical methods of dynamic marginal structural models to compare different treatment strategies for optimising survival. Our findings will provide insights to clinicians on the correct dosing of EPO for haemodialysis patients, and improve the care for patients.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD;RENAL AND UROGENITAL
Title: DEVELOPMENT OF A NON-INVASIVE STRATEGY ENHANCING HAEMATOPOIETIC STEM CELL (HSC) POTENTIAL OF HUMAN UMBILICAL CORD CELLS
Funder: Medical Research Council

Abstract: Definitive haematopoietic stem cells (HSCs) are responsible for the daily generation of billions of mature lymphoid and myeloid cells. Transplantation of one HSC into a myeloablated animal results in a long-term multi-lineage haematopoietic reconstitution. This strong regenerative potential of HSCs is broadly exploited in bone marrow transplantations procedures in clinical settings. HSCs are generated during embryonic development. The aorta-gonad-mesonephros (AGM) region plays an important role in the initiation and expansion of HSCs as has been shown in vitro. We have recently developed a novel ?open? AGM in vitro system which enables the effective initiation and dramatic (150-fold) expansion of HSCs, and importantly allows integration of exogenous cells, in a 3-dimensional co-aggregate culture. Human umbilical cord is an easily accessible source of HSCs, but it contains low numbers of HSCs which limit its value for clinical applications. While useful for children, transplantation into adult patients is significantly less efficient. It is likely that at birth the umbilical cord still represents a ?plastic? stage in haematopoietic development. Published evidence suggests that the umbilical cord endothelium is still haematogenic. This proposal aims to develop non-invasive methods for enhancing the HSC potential of human umbilical cord cells compatible with clinical settings. We will use primary AGM cells and derive a library of immortalised stromal cell lines from the human AGM region. AGM primary stroma and cell lines will be co-cultured with selected cell populations from the umbilical cord, which are phenotypically equivalent to cells developing into HSCs in the AGM region using our novel co-aggregation protocol. Formation of human HSC from umbilical cord cells will be monitored by long-term repopulating assay using severely immunocompromised NSG mice.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Comprehensive Anaemia Programme and Personalized Therapies (CAPPT)
Funder: Department for International Development

Abstract: Anaemia in pregnancy continues to be a significant global health problem, with iron deficiency anaemia (IDA) affecting almost half of the world's pregnant population. Given the adverse outcomes associated with anaemia in pregnancy for both fetus and mother, this problem requires urgent and novel investigation and treatments. Our intervention consists of timely pregnancy detection and tailored behavioural, educational and nutritional advice and oral iron therapy. This will be provided through 2 home visits: at 8-16 weeks and at 22 weeks. Primary research question- Does a home-visiting intervention providing a tailored dosage of oral iron-folate supplementation along with a personalized package of nutrition education and counselling (the CAPPT intervention) supported by community-based participatory learning and action (PLA) women's groups increase haemoglobin levels at 28 weeks of pregnancy, compared with haemoglobin levels in women who undergo routine antenatal care? Study Design- Two non-blinded cluster randomized controlled trials, in rural settings in India and Nepal, run in parallel with many features in common including data collection methods so as to allow some combined analysis. Both trials will include a control (routine care) arm and a combined intervention arm comprising intensive home-based counselling and tailored iron, plus provision of participatory learning and action women's groups (PLA). The mean difference of the 28 weeks HemoCue haemoglobin concentration between groups is the primary outcome in the study. As secondary outcomes we will investigate food allocation, diversity and inequality issues as well as factors that influence non response including; compliance, underlying genetic associations, haemaglobinopathies and infection. The trial will provide proof of concept for a feasible, scalable program that improves diets and reduces anaemia in pregnant women, which could be implemented in high anaemia burden areas in India and Nepal


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: BLOOD;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: SIPHRE Shock Index in Pregnancy: Haemorrhage Risk Evaluation. Shock index as a predictor of adverse outcome in maternal haemorrhage
Funder: Medical Research Council

Abstract: We propose a validation of shock index (SI) as an earlier predictor of adverse outcome from obstetric haemorrhage in LIC. This data could support a future prospective trial to evaluate the use of SI in triage and management of bleeding patients. Since avoidable maternal deaths and near-misses are often related to delays in recognition of hemodynamic compromise it is anticipated that a care bundle that incorporates SI as a triage/referral criteria will improve care. Our prior research has evaluated SI (ratio of HR/systolic BP) in obstetric haemorrhage and sepsis. A prospective study in South Africa validated previously determined thresholds: < 0.9 worked well as a rule out test, >0.9 indicated need for referral, and >1.7 indicated high chance of adverse outcome. Use of the CVSA (a vital signs measurement device which incorporates shock index thresholds) in management was associated with an 80% reduction in hysterectomy (Or 0.21, 95% CI 0.07- 0.66), and in- country analysis in Sierra Leone (SL) showed a reduction in maternal mortality by 60%. Use of SI appears promising- we seek to validate SI on a larger scale in a LIC, where adverse outcomes are more prevalent, to confirm mechanism of benefit. This allows us to trial its prospective use in management with the capacity to impact national and international guidance on the management of obstetric haemorrhage. This is a prospective cohort study, supported by the Ministry of Health and Sanitation in SL, in the main maternity hospital (PCMH) and surrounding units. PCMH has around 7500 deliveries per year, with 95 maternal deaths in 2018. Local researchers will recruit patients diagnosed with obstetric haemorrhage, comparing vital signs at diagnosis and during their admission to outcomes. Area under the receiver-operator-curve predicts whether SI is a superior predictor of adverse outcome (hysterectomy, transfusion>4 units, critical care admission, Hb<70) compared to conventional vital signs.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: BLOOD;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Matrix metalloproteinase activated Multimodal 'Theranostic' Drug Delivery Imaging Agents for thrombosis
Funder: Medical Research Council

Abstract: This proposal contains four aims; (i) the development and validation of nanoparticles, non-toxic quantum dot (QD) based probes that will specifically bind platelets, whilst not affecting the platelet's activation or functional status. Involving the synthesis of InP/ZnS based QDs, synthesizing bifunctional chelates for gadolinium (MRI) and conjugation of antibodies specific for platelets. (ii) Development of a MMP specific mechanism of drug release: including peptide conjugation chemistry between Altepase and QDs through cleaveable peptide sequences, responsive to MMP released from activated platelets. Also including physical studies using MMP enzymes. (iii) Evaluation of the thrombolytic capability of the NP-drug delivery system: Washed platelets and whole blood will be incubated with NPs, with and without Alteplase, and we will use our panel of platelet functional assays to determine how our preparation affects platelet activation. Thrombolytic drugs need to be effective at removing preformed thrombi to re-establish blood flow. Therefore whole blood will be taken in corn trypsin, and thrombi will be formed on collagen in the presence of thrombin, to allow the formation of fibrin rich thrombi. These thrombi will then be post perfused with whole blood containing NPs, with and without Alteplase and thrombus height, surface area, dissolution and fibrin content will be analysed via realtime microscopy. (iv): Evaluation of the NP-drug delivery system in vivo. Mice will go under general anaesthesia, left carotid arteries will be exposed and injury will be induced by applying 1x2 mm filter paper saturated with anhydrous 10% FeCl3. Real time thrombus progression will be recorded using MRI and backed up by intravital microscopy for up to 40 minutes. Once a thrombus is fully formed, NPs with and without Alteplase, will be injected via tail vein and real time thrombolysis (thrombus size and stability) will be monitored.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: BLOOD;STROKE
Title: The differential effect of oral anticoagulant types on the coagulant phenotype of vascular endothelium.
Funder: Medical Research Council

Abstract: Ischaemic stroke, due to thrombotic arterial occlusion constitutes 83% of all strokes. Inflammatory disorders including antiphospholipid syndrome (APS) are strong risk factors for stroke in both the short and long term. Primary and secondary prevention of ischaemic stroke utilises anticoagulants and antiplatelet agents. Differences in their efficacy pose difficult management decisions when choosing therapy. This study will examine the mechanisms underlying these differences and how they will affect therapy. The vitamin K antagonist warfarin is an established and effective anticoagulant for preventing both arterial and venous thrombosis. Direct acting oral anticoagulants (DOACs) inhibiting factor Xa or thrombin have proven equally successful to warfarin in the treatment of venous thrombosis and AF related stroke, but in arterial disease and particularly in APS, they are significantly less effective. This suggests that while warfarin and DOACs have similar effects on plasma coagulation they have different effects on the arterial vessel wall as is expected from their different pharmacology. Using human aortic endothelial cells (EC) from healthy donors as a model for endothelial function, we will determine the procoagulant response of endothelium to inflammatory stimuli and/or IgG isolated from patients with APS in the presence and absence of different anticoagulants. RNA expression, functional assays and molecular cellular techniques will be used to elucidate the mechanisms by which these effects are mediated. Effects of oral anticoagulants on the platelet adhesive phenotype of EC in the presence or absence of inflammatory stimuli will also be assessed. The results will allow identification of optimum targets for new therapies and to individualise therapies for specific patients and specific disorders. Future studies will use patient-derived endothelial cells to confirm these findings and explore longer term effects on endothelial cell function.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: BLOOD;STROKE
Title: Dissecting the mechanisms of pazopanib resistance in soft tissue sarcoma.
Funder: Sarcoma UK

Abstract: Soft tissue sarcomas (STS) are rare malignancies of mesenchymal origin that affect all ages, and comprise 1% of all human cancers. STS usually present locally, but approximately 40% of patients develop recurrent or metastatic disease, which is associated with a median survival of 12 months 1 . Doxorubicin is commonly used as the first line therapy, however response rates in unselected STS are reported to be less than 15% 2 . Strikingly, these statistics have changed little over the last 20 years, highlighting the urgent need for new therapeutic strategies. The multitarget tyrosine kinase inhibitor (TKI) Pazopanib has recently been shown to increase progressionfree survival in advanced and recurrent STS 3 . Clinical data indicates that there are some STS subtypes (e.g. adipocytic sarcomas) that display resistance to this treatment. Even in subtypes that benefit from pazopanib treatment (e.g. synovial sarcomas), there remains a significant patient population that are refractory to therapy. There is currently a poor understanding of the determinants of pazopanib chemoresistance which hinders the development of predictive biomarkers for early patient stratification and the rational identification of new combination targets to overcome resistance. This pilot proposal aims to address this challenge by identifying the molecular mechanisms of intrinsic pazopanib resistance in a panel of STS cell lines of different subtypes using an integrated proteomic strategy. We will employ a targeted phosphoproteomic approach to characterise the kinase signalling networks in STS cell lines prior to and following pazopanib treatment. A bioinformatic analysis of the proteomic, genomic and drug response data will prioritise resistance-causing protein candidates for future experimental validation. Significantly, this project will advance our understanding of the mechanisms of pazopanib resistance and will facilitate the identification of new candidates for prognostic biomarkers and combination therapy in STS patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Studies in Angiosarcoma using Canine Tumours
Funder: Sarcoma UK

Abstract: Angiosarcomas (AS) are rare, aggressive tumours of malignant endothelial cells. Angiogenesis is the process of new blood vessel formation. We hypothesise that angiogenic growth factors are important in the biology of AS and represent potential treatment targets. We have already evaluated two human AS cell lines in vitro, and analysed a panel of 40 archived human AS and benign vascular tumours. Our results require validation in a larger sample set, however human samples are limited and we lack an experimental model that enables in vivo drug studies. Although rare in humans, AS are common in dogs. Through collaborations with the Animal Health Trust (UK) and the Van Andel Research Institute (USA) we have assembled a large cohort of canine AS samples, including tumour blocks and early passage tumour cells. We propose a study of AS and vascular targeted therapy using these canine AS samples. Specifically we propose: 1. mRNA array studies to quantify the expression of angiogenic growth factors and their receptors by canine AS, and to compare results with data from our studies in human AS. 2. in vitro studies of vascular targeted drugs in canine AS early passage tumour cells. 3. to establish canine AS xenografts in mice for in vivo drug studies. It is expected results from these studies will lead to clinical trials for AS in both humans and dogs.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Analysis of Osteolysis in Ewing's Sarcoma and the effect of resorption inhibitors on tumour growth
Funder: Sarcoma UK

Abstract: Ewing's Sarcoma (ES) is characterized by rapid proliferation of tumour cells and rapidly progressive and extensive bone destruction. Osteolysis in ES is carried out by osteoclasts which are formed from monocyte-macrophage precursors in the presence of RANKL and M-CSF. We have shown that ES cells express RANKL (as well as M-CSF and OPG) and that they are capable of inducing osteoclast formation through cell-cell contact by a RANKL-dependent mechanism. We found that ES cells did not express TRAIL and that EC-induced osteolysis was inhibited by bisphosphonates which have been shown to inhibit ES tumour growth. This study will use cell culture, functional assays, and molecular biology to further investigate osteoclast formation in ES and the effect of resorption inhibitors on ES osteolysis and tumour growth. Protein and mRNA expression of osteoclastogenic factors will be determined and cytochemical and functional markers of osteoclast formation measured. The effect of anti-RANKL agents (+/- zoledronate) on ES-induced osteoclast formation and resorption will be determined. The effect of these inhibitors on ES tumour cell proliferation, apoptosis, invasion and migration as well as TRAIL expression will also be analysed. These studies will provide evidence to indicate whether resorption inhibitors could represent a useful adjuvant treatment in ES.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Studies of genetic susceptibility using exome sequencing in patients with sarcoma and an additional primary tumour
Funder: Sarcoma UK

Abstract: Currently there are at least 10 known genes that confer susceptibility to sarcoma and mutations in these genes, like the majority of other cancer susceptibility genes, can result in predisposition to multiple cancers 1 . It is likely that additional susceptibility genes for sarcoma exist and it is likely that these too will cause predisposition to multiple cancers. We aim to assemble germline DNA from a series of 200 individuals who have had sarcoma plus a second primary cancer, as these individuals are likely to be particularly enriched for genetic predisposition factors. We shall sequence the exome (20,000 genes) of these 200 individuals and perform follow-up experiments in order to (i) identify novel sarcoma predisposition genes and (ii) to characterise the contribution of known cancer predisposition genes to presentations of multiple cancers involving sarcoma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Study to investigate correlations between age-dependant pharmacokinetic variation, side-effects of chemotherapy and biomarkers of toxicity in Ewing’s sarcoma.
Funder: Sarcoma UK

Abstract: Ewing sarcoma is a bone cancer most commonly diagnosed in teenagers. Current treatment strategies result in approximately 60% of patients being cured, but with serious side-effects often associated with treatment. Routine tests do not accurately predict who will be cured or will experience increased adverse effects. Survival and toxicity are both highest in younger children and progressively fall with age. The biological correlates of this progressive age-related reduction in survival are not known. However, differences in drug disposition between these patient populations could explain the observed differences in response rates and toxicity following standard treatment. Age-related differences in drug exposure have not previously been studied in Ewing sarcoma as a potential contributor to mortality. The proposed study will investigate differences in pharmacokinetics of the drugs vincristine, ifosfamide, doxorubicin, etoposide and cyclophosphamide in adolescent patients as compared to children and adults with Ewing sarcoma. In addition a panel of blood-borne biomarkers predictive in adults of bone marrow and mucosal toxicity, the most common severe acute toxicities of Ewing sarcoma chemotherapy, will be evaluated in children and adolescents and correlations with pharmacokinetic parameters investigated. Data generated may lead to optimised treatment and allow the prediction of Ewing sarcoma patients most likely to experience side effects of chemotherapy.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS