ORCID Profile
0000-0002-3078-8359
Current Organisation
University of Glasgow School of Medicine
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Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
DOI: 10.1038/NATURE11547
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.BIOCHI.2005.07.003
Abstract: Hepcidin is a liver-expressed antimicrobial and iron regulatory peptide. A number of studies have indicated that hepcidin is important for the correct regulation of body iron homeostasis. The aims of this study were to analyse the expression, trafficking and regulation of human hepcidin in an in vitro cell culture system. Human hepcidin was transfected into human embryonic kidney cells. Immunofluorescence and confocal microscopy analysis revealed that recombinant hepcidin localised to the Golgi complex. Recombinant hepcidin is secreted from the cell within 1 h of its synthesis. Recombinant hepcidin was purified from the cell culture medium using ion-exchange and metal-affinity chromatography and was active in antimicrobial assays. Amino-terminal sequence analysis of the secreted peptide revealed that it was the mature 25 amino acid form of hepcidin. Our results show that recombinant myc-His tagged human hepcidin was expressed, processed and secreted correctly and biologically active in antimicrobial assays.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2013
Abstract: In iduals with adenocarcinoma of the ulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ulla of Vater. Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34 95% CI, 1.69 to 6.62 P .001) and both validation cohorts (HR, 5.65 95% CI, 2.77 to 11.5 P .001 and HR, 2.78 95% CI, 1.25 to 7.17 P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Publisher: Elsevier BV
Date: 07-2012
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2009
DOI: 10.1158/0008-5472.CAN-09-1852
Abstract: Largely owing to widespread deployment of microarray analysis, many of the transcriptional events associated with invasive cell migration are becoming clear. However, the transcriptional drives to invasive migration are likely modified by alternative splicing of pre-mRNAs to produce functionally distinct patterns of protein expression. Heterogenous nuclear ribonucleoprotein (hnRNP A2) is a known regulator of alternative splicing that is upregulated in a number of invasive cancer types. Here, we report that although siRNA of hnRNP A2 had little influence on the ability of cells to migrate on plastic surfaces, the splicing regulator was clearly required for cells to move effectively on three-dimensional matrices and to invade into plugs of extracellular matrix proteins. We used exon-tiling microarrays to determine that hnRNP A2 controlled approximately six in idual splicing events in a three-dimensional matrix-dependent fashion, one of which influenced invasive migration. Here, we show that alternative splicing of an exon in the 5′ untranslated region of a gene termed TP53INP2 is a key event downstream of hnRNP A2 that is necessary for cells to invade the extracellular matrix. Furthermore, we report that the consequences of altered TP53INP2 splicing on invasion are likely mediated via alterations in Golgi complex integrity during migration on three-dimensional matrices. [Cancer Res 2009 (24):9219–27]
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.17.00221
Abstract: Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.
Publisher: Portland Press Ltd.
Date: 10-08-2004
DOI: 10.1042/BJ20040411
Abstract: A detailed study has been carried out on the dependence of folate binding on the concentration of FBP (folate-binding protein) at pH 5.0, conditions selected to prevent complications arising from the pre-existing self-association of the acceptor. In contrast with the mandatory requirement that reversible interaction of ligand with a single acceptor site should exhibit a unique, rectangular hyperbolic binding curve, results obtained by ultrafiltration for the FBP–folate system required description in terms of (i) a sigmoidal relationship between concentrations of bound and free folate and (ii) an inverse dependence of affinity on FBP concentration. These findings have been attributed to the difficulties in determining the free ligand concentration in the FBP–folate mixtures for which reaction is essentially stoichiometric. This explanation also accounts for the similar published behaviour of the FBP–folate system at neutral pH, which had been attributed erroneously to acceptor self-association, a phenomenon incompatible with the experimental findings because of its prediction of a greater affinity for folate with increasing FBP concentration.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NATURE21063
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NATURE16965
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous (2) pancreatic progenitor (3) immunogenic and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
DOI: 10.1038/NATURE24462
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 05-2020
Publisher: Impact Journals, LLC
Date: 11-11-2015
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/NATURE14169
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2020
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2015
DOI: 10.1158/1078-0432.CCR-15-0426
Abstract: Purpose: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The In idualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. Experimental Design: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 lification KRAS wild-type and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Results: Tumor biopsy and archived tumor s les were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 lification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. Conclusions: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options. Clin Cancer Res 21(9) 2029–37. ©2015 AACR.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2017
Publisher: Wiley
Date: 09-05-2014
DOI: 10.1002/IJC.28765
Abstract: The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite licon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Marc Jones.