NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of 2D and 3D Ultrasound Super-Resolution (US-SR) Imaging for the Clinic
Funder: Medical Research Council

Abstract: Non-invasive imaging of the microvasculature is crucial for the early detection and intervention of diseases such as cancer and other microvascular related diseases. This proposal addresses a crucial clinical challenge: the lack of a sensitive, safe, repeatable method for detecting, characterising and monitoring such diseases. Recently developed ultrasound super-resolution (US-SR) is able to resolve microvascular details far beyond the diffraction limit at depth (>10 cm) in vivo. To transfer this technology into society, clinical translation and 3D US-SR development is urgently needed. Aims:. This research is designed to provide advances in areas of maximal clinical relevance through systematically designed experiments, recent technological advances, and clinical guidance and support. The results will provide both validation, and a solid grounding in basic science for the fast developing field of US-SR. The core objectives are: 1)To develop novel advanced, acquisition strategies and real-time software using deep learning, advanced signal processing methods, and the activation of sparse contrast agent to provide improved detection accuracy, localisation rates, and automation. 2)To design, develop and test (in vitro and in vivo) the accuracy and clinical relevance of structural and functional parameters for disease characterisation. 3)To formalise clinical 2D US-SR and establish clinical acceptance. This involves the demonstration of the diagnostic power of US-SR parameters over large clinical datasets from existing studies. 4)To develop and implement clinical 3D US-SR with the aid of advances made in 1)-3), a healthy volunteer pilot study and existing patient studies. By making maximal use of planned or existing trials, I will avoid the need for significant additional human involvement. Throughout this translational project, methods will be evaluated by an extensive network of clinicians and researchers, allowing continuous feedback and ongoing knowledge


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Gene Regulation
Funder: Cancer Research UK

Abstract: In every human cell, the expression of 25,000 genes is precisely regulated to generate the spectrum of cell types required through development and into the adult. We are interested in the signalling pathways that coordinate and regulate gene expression, and how dysregulation of these pathways is a cause or consequence of disease. Our aim is to understand how gene expression is regulated in health and disease, and to use this knowledge to develop and refine therapeutic approaches. Our focus is on the RNA cap, a structure found on pre-mRNA and non-coding RNA that protects RNA and recruits factors involved in processing and translation. A series of RNA capping enzymes catalyses cap formation, predominantly as the transcript is being synthesised. We are interested in how these RNA capping enzymes are regulated during development and in the adult, and the impact that this has on gene expression. Currently, we are investigating RNA cap regulation in embryonic stem cell differentiation, during T cell activation and following oncogene dysregulation in cancer models. Regulation of the RNA cap can have potent effects on cell function and fate decisions via the regulation of specific gene families. We characterise the biochemical configuration of capping enzyme complexes in different cell types or disease states, follow how these configurations change during differentiation and disease, and determine the impact on gene expression and cell function and fate decisions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Data-driven risk and prognosis prediction from linked electronic health care records: Pancreatic cancer as an exemplar
Funder: Barts Charity

Abstract: Pancreatic Cancer (PaC) is a highly intractable malignancy, with incidence nearly equaling mortality in patients. Aggressive tumour biology and the lack of distinctive cancer-specific symptoms, such as weight loss, obstructive jaundice and abdominal pain, during early-stage of the disease have fostered dismal survival rates in PaC, with only 7.3% of patients in England surviving to 5 years from diagnosis (1). This poor survival rate is largely associated with late-stage diagnosis when surgical resection, the only treatment option with curative intent, becomes infeasible. Electronic health records (EHR) routinely generated by the hospitals and GPs during the normal care of patients are a rich resource that could help us learn how to tailor treatments for individual patients and create provisions for better healthcare. However, only a fraction of the wealth of information contained in the EHR is currently utilised for diagnosis, treatment and other clinical decisions. The project proposed here intends to unlock the potential of linked primary, secondary and tertiary care EHR to enable improved management of pancreatic cancer. By exploring putative etiological factors (commonly referred to as exposures or risk factors including treatments) our study will yield a more accurate risk measure for PaC. By improving our understanding of how exogenous risk factors contribute to the onset and progression of PaC, this study constitutes a critical step in informing evidence-based clinical practice. This proposal will create a timely framework for linking hospital and GP records to address an unmet clinical challenge. Solving this data linkage challenge will deliver significant benefits to patients, the North East London population, and health care providers by developing and evaluating data-driven clinical applications for direct care and service delivery. It will contribute to objectives in the 10-year NHS plan, including earlier diagnosis of cancer. It will also advance the understanding of cancer and multimorbidity in an ethnically diverse community, and thereby building a framework that could be expanded to study other challenging complex diseases.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: The Structure, Chemistry and Function of the Genome
Funder: Cancer Research UK

Abstract: Background Our goals are to gain molecular and mechanistic insights into the chemistry and structure of nucleic acids and to understand how these influence genome function in normal biology and cancer. Methods Our programme is uniquely interdisciplinary combining our strengths in molecular biophysics, organic chemistry and chemical biology with genomics, cellular and molecular biology and also computational chemistry and bioinformatics. Aims 1. DNA G-quadruplex structures (G4s) in transcription and chromatin biology We and others have shown that G4s are endogenous features of human cells linked with transcription and chromatin biology. G4s are more abundant in cancers and are located in oncogene promoters and telomeres. New avenues for therapeutic intervention have arisen through G4-targeting by small molecules to kill cells. We aim to elucidate G4 roles and influence on genome function and cancer processes. Main goals: a) Understanding G4 mechanisms in transcription b) Exploring relationships between G4s, chromatin and epigenetics c) Determining G4 relevance to cancer signatures and exploiting synthetic lethality 2. Epigenetics of cytosine (and other base) modifications in DNA Chemical modifications to nucleobases are critical regulators of gene expression and inheritance. Epigenome changes are also intimately associated with cancer progression. We have developed innovative chemistry-based technologies for accurate quantification and single-base resolution mapping of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). We aim to elucidate the function of these (and other) modified bases in normal biology, development and cancer. Main goals: a) Investigating 5fC and 5caC roles in genome regulation b) Determining the full extent of the DNA epigenetic code c) Understanding the importance of DNA epigenetics in cancer 3. RNA G-quadruplex structures in global translational regulation RNA G4s (rG4s) are present in endogenous cellular RNA. We have previously shown that rG4s in the 5’UTRs of oncogene mRNAs influence translation. Increased translation is also a cancer hallmark and we have recently discovered that rG4s may control ribosomal protein synthesis to regulate global cellular translation. We aim to understand the mechanism of protein synthesis regulation by rG4s as a possible route for cancer interventions. Main goals: a) Determining the mechanisms of ribosomal protein translation by rG4s b) Exploring how rG4s control global translation and response to stress. How the results of this research will be used Our research is focused on fundamental mechanisms. We expect our findings will provide tools and data to enable new approaches for the intervention, early detection and diagnosis of cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Molecular Mechanisms of Hedgehog Morphogen Signalling at the Cell Surface - Studentship
Funder: Cancer Research UK

Abstract: The Hedgehog (HH) morphogen pathway plays a pivotal role in tissue patterning during embryogenesis, and in tissue homeostasis and regeneration during adulthood. Due to its biological valence, a misregulation can lead to birth defects and tumourigenesis. Moreover, many of the mutations found in human tumours such as basal cell carcinoma, rhabdomyosarcoma and medulloblastoma, affect the function of Patched (PTCH1), a 12-pass transmembrane protein and main receptor for the secreted HH morphogen. PTCH1 controls the HH signal transduction in side the cell by regulating the G protein coupled receptor and oncoprotein Smoothened (SMO). However, how PTCH1 suppresses SMO function and how the extracellular HH morphogen releases this effect are only poorly understood. One hypothesis is that PTCH1 functions as a transporter for cholesterol or a related derivative, that is necessary for SMO activation. However, experimental proof is still lacking. This project focuses on the molecular understandings of this fascinating signalling pathway, to shed light into the basic cancer mechanisms In conclusion, understanding and knowing the molecular basis which drive a biological pathway is essential to counteract associated pathologies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Molecular Mechanisms of the Kinetochore and cell cycle
Funder: Cancer Research UK

Abstract: The project will involve reconstituting the process of chromosome segregation in vitro to understand the structure of the chromosome segregation machinery and to understand its biochemistry and biophysics. Specifically we will reconstitute the centromere-kinetochore-microtubule structure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Elucidating the mechanism of RNA dependent DNA damage response and its role in cancer
Funder: Cancer Research UK

Abstract: Studentship associated with a programme: Background Efficient DNA damage repair is a fundamental process for every living organism. The accumulation of DNA damage leads to a variety of diseases, particularly cancer. Therefore, understanding of the molecular mechanisms of DNA damage repair is of great importance. Transcription is a fundamental and highly regulated process. The CTD of RNAPII consists of 52 repeats of the consensus heptad Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Phosphorylation of Ser2 and Ser5 (S2/5P) are essential for transcription of protein coding genes. However, phosphorylation of Tyr1 (Y1P) has only recently been described and its physiological context remains unknown. We showed that RNAPII Y1P and the RNase III enzyme Dicer phosphorylated at residue serine1016 are specifically recruited to DSBs. The RNA interference (RNAi) pathway is essential for the processing of microRNAs (miRNAs). Recent evidence points to the existence of additional non-canonical nuclear RNAi functions including genome maintenance and DNA repair. However, the coordinated function of transcription, RNA and RNAi in DNA damage response (DDR) is poorly understood. Aims: The goal of my research program is to understand the mechanism of RNA dependent DDR and how this process is regulated. Our specific aims are: 1. Regulation of DNA damage induced transcription 2. Analysis of DNA induced RNA 3. Molecular mechanism of DNA damage derived RNA processing 4. Function of RNA in DNA repair Methods: In Aim 1, we will employ localized DSBs using tamoxifen-inducible restriction enzyme (AsiSI-ER) in U2OS cells, allowing sequence-specific analysis of transcription in context of the RNAPII CTD phosphorylation status. We will perform mNET-seq (sequencing of mammalian nascent elongating transcripts) and 4-thiouridine-(4sU)-tagging (sequencing of nascent RNA after in vivo metabolic labelling with 4sU). Both protocols are established in our laboratory. In Aim 2, we will identify proteins that specifically bind to CTD Y1P upon DNA damage by mass spectroscopy. CTD Y1P kinase is unknown, therefore we will focus on kinases in our screen. The most significant candidates will be analyzed further for their function. In Aim 3, we will test RNAi factors for their role in damage derived RNA processing. To do so we will employ PAR-clip and subcellular compartmentalization assays. How the results of this research will be used: Understanding regulatory mechanisms of DNA damage response will provide key information about genome stability, and hence cancer biology. Proteins and RNA molecules identified in this study may be used as new diagnostic markers and help to identify effective strategies to treat and prevent cancers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Beatson Unallocated Research Services
Funder: Cancer Research UK

Abstract: BICR core facilities not allocated to specific labs. Coded to overall lab profile


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Computational Biology and Integrative Genomics
Funder: Cancer Research UK

Abstract: We search for integrated genomic blueprints that enable us to predict how cancer will evolve and respond to treatment. High throughput technology has supported a scientific revolution both in molecular biology and clinical research. In molecular biology, and more specifically in both cancer and radiation biology, it is now possible to acquire data at the whole genome level, and to characterise a genomic blueprint for different cancer types. This has allowed us to ask questions on how the cancer genome is regulated. Most importantly we are beginning to understand how and where the blueprint of the genome is functional and what the biological and clinical implications of this function are. In translational and clinical research it is becoming increasingly possible to acquire both genomic and disease imaging data, and this combination can provide further understanding of the molecular and clinical cancer phenotype. This revolution has enabled the accumulation of cancer genomic big data and related knowledge at a speed never experienced before in science. The knowledge generated with this big data is being increasingly organised in both specialist and general knowledge databases which can be interrogated by computational tools. We are investigating integrative approaches to combine results from functional assays, systems level approaches and clinical knowledge with genomics (DNA) and transcriptomic (RNA) data. To achieve this we apply a wide range of sophisticated computational and statistical techniques to analyse large clinical cohorts. Our research sits at the interface between genomics, imaging and biomarkers and it is applied to molecular and radiation oncology. Our more recent work focuses on next generation sequencing techniques and high content screening, and the development of tools to aid the translation of this big data generated knowledge into beneficial use in the clinic for treatment of patients. http://www.radiationoncology.ox.ac.uk/research/francesca-buffa


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Analysis of the interplay between replication stress and immune responses in SMARCA4 and ARID1A mutant cells
Funder: Wellcome Trust

Abstract: Cancer cells are growing and dividing very rapidly. Rapid division is stressful, and can result in signals being sent to the immune system. In this case, therapies that help the immune system (immunotherapy) to attack the cancer cells are very useful. The SWI/SNF complex is a set of proteins in the cell that help to protect the DNA from stress caused by rapid division. This complex is frequently lost in cancer cells. Here, I will investigate whether by helping cells deal with the stress of dividing, the SWI/SNF complex prevents the immune system from turning on. By understanding this, we can have a better idea about which cancers will respond best to immunotherapy, and what other therapies might work well in combination with immunotherapy for these cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Single-cell and computational biology
Funder: Cancer Research UK

Abstract: Our research focusses on developing the computational and statistical tools necessary to exploit high-throughput genomics data in order to understand the regulation of gene expression and to model developmental and evolutionary processes. Within this context, we focus on work on three specific areas. Firstly, we want to understand how the divergence of gene expression levels is regulated. By associating changes in expression with a specific regulatory mechanism, critical insights into speciation and differences in phenotypes between individuals can be obtained. Second, we want to use gene expression as a definition of the molecular fingerprint of individual cells to study the evolution of cell types. By comparing the molecular fingerprint associated with a particular tissue across species, it is possible to decipher whether specific cell types arise de novo during speciation or whether they have a common evolutionary ancestor. Thirdly, we want to model spatial variability in gene expression levels within a tissue or organism. By modelling such variability, heterogeneous patterns of expression within a cell-type can be identified, potentially allowing new cell-types, perhaps with novel functions, to be uncovered. Additionally, the extent of heterogeneity present across a tumour can also be studied using such approaches.These three strands of research are brought together by single-cell sequencing technologies. By studying variability in gene expression (and other genome-wide characteristics) at a single-cell level, our ability to assay regulatory variation, molecular fingerprints and spatial patterns of expression will be revolutionised. As a key member of the Sanger-EBI Single Cell Genomics Centre we are closely involved in data generation and in using these data, especially single-cell RNA-sequencing, to answer numerous exciting biological questions. However, to exploit these data to the fullest extent, it is critical to develop the appropriate statistical and computational tools - this is one of the key challenges we face in the next few years.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Investigating New Therapeutic Targets in Myeloid Leukaemia
Funder: Cancer Research UK

Abstract: Over the last 30 years, cytotoxic therapy has been the standard of care for Acute Myeloid Leukaemias (AMLs). Unfortunately, more often than not, this therapy fails to cure patients. Therefore, there is a pressing need for the development of more specific and efficient therapies. To this end, my laboratory undertakes two integrated research programs emanating from my expertise in developmental haematopoiesis: a) investigating the mechanisms driving the initiation and maintenance of leukaemia and b) extending the understanding of normal haematopoietic system development. Our work will improve patient outcomes by identifying and validating therapeutic targets for leukaemia treatment as well as by generating cells for adoptive cancer immunotherapies. My lab has made seminal contributions to understanding the function of RUNX1, one of the most mutated genes in AMLs. We also accumulated evidences that a transcriptional co-activator of RUNX1, the histone acetyltransferase MOZ, is critical for sustaining some of the most aggressive AMLs and therefore represents a novel potential therapeutic target. Additionally, we recently discovered that EYA1 and SIX1, two members of the retinal determination gene network, play an essential role in maintaining such AMLs. We will address the following questions in three inter-related work-packages. WP1: Can MOZ, and its HAT activity, be therapeutically targeted to alter the maintenance of AMLs, and other cancers? WP2: How does the bipartite SIX1/EYA1 transcription factor complex participate in the development and maintenance of AMLs? WP3: What are the unique components of the molecular programmes underpinning haematopoietic lineage commitment? This is an essential prerequisite for the production of blood cells for adoptive immunotherapies? Experimental Approaches These research questions will be addressed using state-of-the-art sequencing technologies, in vitro and in vivo model systems and genetic strategies. We will access patient samples through the Manchester Cancer Research Centre (MCRC) biobank, and take advantage of CRUK-MI capabilities to explore the translational potential of our research. Deliverables towards patient impact 1. Validation of MOZ as a therapeutic target in AMLs and other cancers 2. Revealing the role of SIX1/EYA1 in AMLs to guide development of potential therapeutic strategies targeting this complex or its downstream effectors. 3. Revealing the molecular programmes driving generation of specific blood cells to design protocols for efficient production of HSCs or immune cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE