A5082051357- Colorectal and Anal Carcinomas
- Colorectal Cancer Treatments and Studies
- Gastrointestinal Tumor Research and Treatment
- Muscle Physiology and Disorders
- Cancer Immunotherapy and Biomarkers
- MicroRNA in disease regulation
- Immune Cell Function and Interaction
- Extracellular vesicles in disease
- RNA Research and Splicing
- Immune cells in cancer
- RNA Interference and Gene Delivery
- Genetic factors in colorectal cancer
- Lung Cancer Treatments and Mutations
- CRISPR and Genetic Engineering
- Amyotrophic Lateral Sclerosis Research
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- CAR-T cell therapy research
- Cardiomyopathy and Myosin Studies
- Adipose Tissue and Metabolism
- Circular RNAs in diseases
- Cytokine Signaling Pathways and Interactions
- Neurogenetic and Muscular Disorders Research
- Biotin and Related Studies
- PARP inhibition in cancer therapy
Merck (Germany)
2021-2024
AstraZeneca (United Kingdom)
2019-2023
University of Oxford
2014-2022
AstraZeneca (Netherlands)
2021
National Hospital for Neurology and Neurosurgery
2017-2021
University College London
2017-2021
AstraZeneca (Canada)
2018
Oxford Fertility
2015
Yale University
2012
Members of the tripartite interaction motif (TRIM) family E3 ligases are emerging as critical regulators innate immunity. To identify new regulators, we carried out a screen 43 human TRIM proteins for ability to activate NF-κB, AP-1, and interferon, hallmarks many immune signaling pathways. We identified 16 that induced NF-κB and/or AP-1. found one these, TRIM62, functions in TRIF branch TLR4 pathway. Knockdown TRIM62 primary macrophages led defect TRIF-mediated late interferon production...
Extracellular microRNAs (miRNAs) are under investigation as minimally-invasive biomarkers for a wide range of disease conditions. We have recently shown in mouse model the progressive muscle-wasting condition Duchenne muscular dystrophy (DMD) that set highly elevated serum miRNAs reflects regenerative status muscle. These promising monitoring DMD progression and response to experimental therapies. The gold standard miRNA detection methodology is Reverse Transcriptase-quantitative Polymerase...
Antisense oligonucleotides (ASOs) have the potential to revolutionize medicine due their ability manipulate gene function for therapeutic purposes. ASOs are chemically modified and/or incorporated within nanoparticles enhance stability and cellular uptake, however, a major challenge is poor understanding of uptake mechanisms, which would facilitate improved ASO designs with enhanced activity reduced toxicity. Here, we study mechanism three therapeutically relevant (peptide-conjugated...
<h3>Background</h3> The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy recent years. This has driven interest identifying small-molecule-immunotherapy combinations increase the proportion of responses. Murine syngeneic models, which have functional immune system, represent an essential tool for pre-clinical evaluation new immunotherapies. However, response varies...
PI3K inhibitors with differential selectivity to distinct isoforms have been tested extensively in clinical trials, largely target tumor epithelial cells. signaling also regulates the immune system and inhibition of PI3Kδ modulate microenvironment pre-clinical mouse models by relieving T-regs-mediated immunosuppression. as a class specifically are associated immune-related side effects. However, impact mixed immunology is under-explored. Here we examine effects AZD8835, dual PI3Kα/δ...
Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments currently clinical trials. By using a comprehensive high-resolution mass spectrometry approach western blot validation, we found that two fragments of myofibrillar structural protein myomesin-3 (MYOM3) abnormally present sera Duchenne (DMD) patients, limb-girdle type 2D (LGMD2D) their respective animal models. Levels MYOM3 were assayed therapeutic model systems: (1) restoration...
Multiple studies have described extracellular microRNAs (ex-miRNAs) as being remarkably stable despite the hostile environment, when stored at 4ºC or lower. Here we show that many ex-miRNAs are rapidly degraded incubated 37ºC in presence of serum (thereby simulating physiologically relevant conditions). Stability varied widely between miRNAs, with half-lives ranging from ~1.5 hours to more than 13 hours. Notably, ex-miRNA calculated two different biofluids (murine and C2C12 mouse myotube...
There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification novel protein has been limited due massive complexity serum proteome and presence a small number very highly abundant proteins. Here we have utilised aptamer-based proteomics approach profile 1,129 proteins wild-type mdx (dystrophin deficient) mice. The levels 96 were found significantly altered (P < 0.001, q...
MyomiRs are muscle-specific microRNAs (miRNAs) that regulate myoblast proliferation and differentiation. Extracellular myomiRs (ex-myomiRs) highly enriched in the serum of Duchenne Muscular Dystrophy (DMD) patients dystrophic mouse models consequently have potential as disease biomarkers. The biological significance miRNAs present extracellular space is not currently well understood. Here we demonstrate ex-myomiR levels elevated perinatal muscle development, during regenerative phase follows...
Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sequencing in four muscle types serum from wild-type, dystrophic mdx, mdx mice which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs...
Abstract Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes mortality. Antisense oligonucleotides (AOs) are promising therapy, restoring functional dystrophin protein exon skipping. However, major limitation with current AOs absence of correction heart. Pip peptide-AOs demonstrate high activity cardiac muscle. To determine their...
MicroRNAs (miRNAs) are short RNA molecules which regulate gene expression in eukaryotic cells, and abundant stable biofluids such as blood serum plasma. As such, there has been heightened interest the utility of extracellular miRNAs minimally invasive biomarkers for diagnosis monitoring a wide range human pathologies. However, quantification is subject to number specific challenges, including relatively low content biofluids, possibility contamination with proteins (including RNases PCR...
The absence of the dystrophin protein in Duchenne muscular dystrophy (DMD) results myofiber fragility and a plethora downstream secondary pathologies. Although variety experimental therapies are development, achieving effective treatments for DMD remains exceptionally challenging, not least because pathological consequences loss incompletely understood. Here we have performed proteome profiling tibialis anterior muscles from two murine models (
Abstract Purpose: Peposertib—an orally administered DNA-dependent protein kinase inhibitor—has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) assessed its safety efficacy locally advanced rectal cancer. Patients Methods: were treated for 5 5.5 weeks with 50- 250-mg once daily, capecitabine 825 mg/m2...
Abstract Background Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex‐miRNAs) are putative, minimally invasive biomarkers DMD. Specific ex‐miRNAs (e.g. miR‐1, miR‐133a, miR‐206, and miR‐483) highly up‐regulated in the serum DMD patients dystrophic animal models restored to wild‐type levels following exon skipping‐mediated rescue mdx mice. As such, promising pharmacodynamic skipping efficacy. Here, we...
Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of inhibitors. However, how inhibitors function in different tumor microenvironments (TME) activate specific is underexplored. The effect the novel inhibitor AZD3458 was assessed preclinical models. enhanced antitumor activity 4T1, CT26, MC38 syngeneic models, increasing CD8+ T-cell activation status. Immune TME biomarker analysis tumors...
Therapies that restore dystrophin expression are presumed to correct Duchenne muscular dystrophy (DMD), with antisense-mediated exon skipping being the leading approach. Here we aimed determine whether using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform localization, together correction putative DMD serum and muscle biomarkers. Dystrophin-deficient
Whole-exome sequencing (WES) is widely used in clinical settings; however, the exploration of its use pharmacogenomic analysis remains limited. Our study compared variant callings for 28 core absorption, distribution, metabolism and elimination genes by WES array-based technology using trials samples. The results revealed that had a positive predictive value 0.71–0.92 sensitivity single-nucleotide variants between 0.68 0.95, with technology, commonly targeted regions PhamacoScan™ assay....
Abstract Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing therapies. However, identification SL interactions challenging, due to a large number possible pairs, inherent noise and confounding factors the observed signal. To discover robust interactions, we devised SLIDE-VIP, novel framework combining eight statistical tests, including new patient data-based test iSurvLRT. SLIDE-VIP leverages multi-omics data from four different sources:...
Article5 May 2022Open Access Transparent process A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability Elizabeth Kuczynski Corresponding Author [email protected] orcid.org/0000-0002-6924-6848 Oncology R&D, AstraZeneca, Cambridge, UK Contribution: Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, review & editing Search for more papers by this author Giulia...