A5031535754- Urological Disorders and Treatments
- Renal and related cancers
- Pancreatic function and diabetes
- Melanoma and MAPK Pathways
- Tissue Engineering and Regenerative Medicine
- Neonatal Respiratory Health Research
- Microbial metabolism and enzyme function
- Wnt/β-catenin signaling in development and cancer
- Computational Drug Discovery Methods
- Renal cell carcinoma treatment
- HER2/EGFR in Cancer Research
- Urinary Bladder and Prostate Research
- Pancreatic and Hepatic Oncology Research
- Pediatric Urology and Nephrology Studies
- Congenital heart defects research
- Cancer, Hypoxia, and Metabolism
- Cancer-related gene regulation
- Genetic and Kidney Cyst Diseases
- Click Chemistry and Applications
- Pluripotent Stem Cells Research
- Genetic Syndromes and Imprinting
- Colorectal Cancer Treatments and Studies
- Cancer Research and Treatments
- Biochemical Acid Research Studies
- Radiomics and Machine Learning in Medical Imaging
University of Manchester
2019-2025
Henry Royce Institute
2019-2025
University College London
2024
Manchester Academic Health Science Centre
2019-2024
University of the Witwatersrand
2024
South African Medical Research Council
2024
Genomics (United Kingdom)
2024
Manchester University NHS Foundation Trust
2019-2024
Escola Superior de Saúde Egas Moniz
2023
Cancer Research UK Manchester Institute
2019-2021
Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition 18 murine tissues 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals heterogeneity across tumors, identifies coordinated between immune cell subsets in pancreatic ductal adenocarcinoma. Expression CD105 demarks two stable...
BRAF and MEK inhibitors are effective in mutant melanoma, but most patients eventually relapse with acquired resistance, others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family (SFK) signaling or NRAS, which drive paradoxical of the pathway. We describe pan-RAF (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not activation MEK/ERK NRAS melanoma. They melanoma cells...
Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that regulates epidermal growth factor receptor (EGFR) to drive progression. We show EGFR suppressing TGFβ1 signalling through secreted protease HTRA1. This increases expression of Matrilin2 (MATN2), an EGF-like domain-containing protein traps at cell surface facilitate its activation EGF. describe a pharmacological...
Lysyl oxidase (LOX) is a secreted copper-dependent amine that cross-links collagens and elastin in the extracellular matrix critical mediator of tumor growth metastatic spread. LOX target for cancer therapy, thus search therapeutic agents against has been widely sought. We report herein medicinal chemistry discovery series inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided initial hits. Structure–activity relationship (SAR) studies led to AMT...
Background Rare early-onset lower urinary tract (REOLUT) disorders affect the ureter, bladder, or urethra and manifest before birth in childhood. Monogenic causes have been reported a subset of such individuals. Objectives A possible genetic cause was considered child with megaureter who had syndromic features. Subjects methods Whole-exome sequencing undertaken individuals megaureter. Immunohistochemistry performed tissues unaffected human fetuses. Results The index case presented at 6...
Myocardin (MYOCD) is the founding member of a class transcriptional coactivators that bind serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac development. Insights into molecular functions MYOCD have been obtained from cell culture studies, date, knowledge about vivo roles comes exclusively experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance pathogenic variants. This manifested as...
Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or heparanase (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that syndrome neural basis, but it is unknown whether defects urinary innervation are present. We hypothesized features peripheral neuropathy the bladder. Mice with homozygous targeted Lrig2 mutations had resembling those found syndrome. There was no anatomical...
Urofacial, or Ochoa, syndrome (UFS) is an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against undilated outflow tract. It also features abnormal grimace. Half of individuals UFS carry biallelic variants in
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or functional impairment urinary voiding. About three out 10,000 pregnancies are affected. Although several monogenic causes have been defined, it unknown whether congenital LUTO has a cause. Exome sequencing in family with four affected individuals urethra identified rare nonsense variant (c.2557C>T [p.Arg853∗]) BNC2, encoding basonuclin 2, tracking over generations. Re-sequencing...
The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation cross-links fibrillar elastin and collagens leading to matrix (ECM) stabilization. These enzymes have also been implicated tumor progression metastatic disease thus become an attractive therapeutic target for many types invasive cancers. Following our recently published work on discovery aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein...
Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2 , coding for secreted protein heparanase-2, are described around half families genetically studied. Hpse2 mutant mice have aberrant nerves. We sought to expand genotypic spectrum UFS make insights into its pathobiology. Sanger sequencing, next generation sequencing microarray analysis were...
Rare early-onset lower urinary tract disorders include defects of functional maturation the bladder. Current treatments do not target primary pathobiology these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, bladder does empty fully because incomplete relaxation its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants HPSE2 , encoding heparanase-2. This protein detected in pelvic ganglia,...
Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency melanoma and colorectal carcinoma. We recently reported on the development inhibitors based a tripartite A−B−C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present design, synthesis, optimization new series different that has been modified by introduction range novel binders (A ring). The binding moiety enabled compounds low nanomolar potencies both...
Previous studies in xenopus and zebrafish (zf) provide a detailed description of the embryonic role phosphate transporter slc20a1a early pronephric kidney formation. The recent identification SLC20A1 as monoallelic candidate gene for cloacal exstrophy further suggests its involvement lower urinary tract urorectal development. However, knowledge about formation is poor. To broaden our understanding impact development we induced morpholino oligonucleotide (MO) knockdown orthologue slc20a1a....
Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy widely studied. In contrast, pathobiology urinary bladder less understood despite dysfunctional voiding being common in DM. We hypothesised that cystopathy has a characteristic molecular signature. therefore studied bladders hyperglycaemic polyuric rats with streptozotocin (STZ)-induced Sixteen weeks after induction DM, as assessed by RNA arrays, wide-ranging changes gene expression occurred DM...
Cancer prognostics using tumour transcriptomics is a promising precision medicine approach for helping decisions during cancer treatment. However, currently used prognostic biomarkers still have low predictive power. This work tested the potential of applying machine learning (ML) algorithms generating patients' survival on lung, breast, and kidney datasets. We evaluated performance models generated by ML reported their optimal sensitivity, specificity, accuracy, computed ROC-AUC. The...
KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% colorectal cancers and ∼20% non-small-cell lung cancers. There has been recent progress targeting
We describe the design, synthesis, and optimization of a series new inhibitors V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), kinase whose mutant form (V600E) is implicated in several types cancer, with particularly high frequency melanoma. Our previously described tripartite A−B−C system (where A hinge binding pyrido[4,5-b]imidazolone system, B an aryl spacer group, C heteroaromatic group) were potent against purified V600EBRAF vitro but less accompanying cellular assays....
Abstract Oncogenic BRAF is a critical driver of proliferation and survival thus validated therapeutic target in cancer. We have developed potent inhibitor, termed 1t (CCT239065), the mutant protein kinase, V600EBRAF. inhibits signaling downstream V600EBRAF cancer cells, blocking DNA synthesis, inhibiting proliferation. Importantly, we show that considerably more selective for mutated cell lines compared with wild-type lines. The inhibitor well tolerated mice exhibits excellent oral...
Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but genetic architecture this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) 132 unrelated male PUV cases and 23,727 controls diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (p=7.8 × 10-12; OR 0.4) 6p21.1 (p=2.0 10-8; 7.2), that were replicated an independent European cohort 395 4151...
Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that functional effects morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for ligands, as well Tgfbr1 Tgfbr2 receptors, were detected by quantitative polymerase chain reaction embryonic mouse ureters collected over a wide range of stages. As assessed situ...
Abstract CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in . Affected presented an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS and congenital of the kidneys urinary tract (CAKUT) (3/12) CAKUT only (2/12). Computational simulation 3D protein structure suggests position identified to be implicated penetrance phenotype expression....
Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic malformations (DKMs). To understand their pathobiology, we generated heterozygous mutant organoids from CRISPR-Cas9 gene-edited embryonic stem cells (ESCs) and induced pluripotent (iPSCs) reprogrammed family with HNF1B-associated DKMs. Mutant contained enlarged malformed tubules displaying deregulated cell...