ORCID Profile
0000-0002-6275-3433
Current Organisation
QIMR Berghofer Medical Research Institute
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Publisher: American Chemical Society (ACS)
Date: 16-07-2019
DOI: 10.1021/ACS.JPROTEOME.9B00242
Abstract: Cholangiocarcinoma (CCA) is a major health problem in northeastern Thailand. The majority of CCA cases are clinically silent and difficult to detect at an early stage. Although abdominal ultrasonography (US) can detect premalignant periductal fibrosis (PDF), this method is not suitable for screening populations in remote areas. With the goal of developing a blood test for detecting CCA in the at-risk population, we carried out serum protein biomarker discovery and qualification. Label-free shotgun proteomics was performed on depleted serum s les from 30 participants (
Publisher: Springer Science and Business Media LLC
Date: 30-10-2023
Publisher: Frontiers Media SA
Date: 18-12-2018
Publisher: Wiley
Date: 11-05-2014
Abstract: Rapidly developing proteomic tools are improving detection of deregulated kallikrein-related peptidase (KLK) expression, at the protein level, in prostate and ovarian cancer, as well as facilitating the determination of functional consequences downstream. MS-driven proteomics uniquely allows for the detection, identification, and quantification of thousands of proteins in a complex protein pool, and this has served to identify certain KLKs as biomarkers for these diseases. In this review, we describe applications of this technology in KLK biomarker discovery and elucidate MS-based techniques that have been used for unbiased, global screening of KLK substrates within complex protein pools. Although MS-based KLK degradomic studies are limited to date, they helped to discover an array of novel KLK substrates. Substrates identified by MS-based degradomics are reported with improved confidence over those determined by incubating a purified or recombinant substrate and protease of interest, in vitro. We propose that these novel proteomic approaches represent the way forward for KLK research, in order to correlate proteolysis of biological substrates with tissue-related consequences, toward clinical targeting of KLK expression and function for cancer diagnosis, prognosis, and therapies.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2018
Publisher: American Diabetes Association
Date: 29-08-2017
DOI: 10.2337/DC17-0911
Abstract: To assess the ability of plasma apolipoprotein (apo) A-IV (apoA4), apo C-III, CD5 antigen-like (CD5L), complement C1q subcomponent subunit B (C1QB), complement factor H–related protein 2, and insulin-like growth factor binding protein 3 (IBP3) to predict rapid decline in estimated glomerular filtration rate (eGFR) in type 2 diabetes. Mass spectrometry was used to measure baseline biomarkers in 345 community-based patients (mean age 67.0 years, 51.9% males) from the Fremantle Diabetes Study Phase II (FDS2). Multiple logistic regression was used to determine clinical predictors of rapid eGFR decline trajectory defined by semiparametric group-based modeling over a 4-year follow-up period. The incremental benefit of each biomarker was then assessed. Similar analyses were performed for a ≥30% eGFR fall, incident chronic kidney disease (eGFR & mL/min/1.73 m2), and eGFR decline of ≥5 mL/min/1.73 m2/year. Based on eGFR trajectory analysis, 35 participants (10.1%) were defined as “rapid decliners” (mean decrease 2.9 mL/min/1.73 m2/year). After adjustment for clinical predictors, apoA4, CD5L, and C1QB independently predicted rapid decline (odds ratio 2.40 [95% CI 1.24–4.61], 0.52 [0.29–0.93], and 2.41 [1.14–5.11], respectively) and improved model performance and fit (P & 0.001), discrimination (area under the curve 0.75–0.82, P = 0.039), and reclassification (net reclassification index 0.76 [0.63–0.89] integrated discrimination improvement 6.3% [2.1–10.4%]). These biomarkers and IBP3 contributed to improved model performance in predicting other indices of rapid eGFR decline. The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes.
Publisher: Wiley
Date: 12-03-2021
Abstract: To identify glucocorticoid‐responsive proteins measurable in human serum that may have clinical utility in therapeutic drug monitoring and the diagnosis of cortisol excess or deficiency. A phased biomarker discovery strategy was conducted in two cohorts. Secretome from peripheral blood mononuclear cells (PBMC) isolated from six volunteers after ex vivo incubation ± dexamethasone (DEX) 100 ng/mL for 4 h and 24 h was used for candidate discovery and qualification using untargeted proteomics and a custom multiple reaction monitoring mass spectrometry (MRM‐MS) assay, respectively. For validation, five candidates were measured by immunoassay in serum from an independent cohort ( n = 20), s led at 1200 h before and after 4 mg oral DEX. The discovery secretome proteomics data generated a shortlist of 45 candidates, with 43 measured in the final MRM‐MS assay. Differential analysis revealed 16 proteins that were significant in at least one of two time points. In the validation cohort, 3/5 serum proteins were DEX‐responsive, two significantly decreased: lysozyme C ( p 0.0001) and nucleophosmin‐1 ( p 0.01), while high mobility group box 2 significantly increased ( p 0.01). Using an ex vivo proteomic approach in PBMC, we have identified circulating glucocorticoid‐responsive proteins which may have potential as serum biomarkers of glucocorticoid activity.
Publisher: Proceedings of the National Academy of Sciences
Date: 19-06-2017
Abstract: The hypoxic microenvironment in solid tumors is known to increase the aggressiveness of cancer cells by enhancing proliferative and metastatic potential and reduces the efficacy of radiation and chemotherapy. Previous studies have shown that G9a protein accumulates in hypoxic conditions. However, neither a detailed molecular mechanism nor its functional role has been elucidated so far. This study investigates the role G9a plays in gene expression in hypoxic conditions and its impact on tumor growth. G9a inhibition studies and the metaanalysis of G9a-suppressed gene signature using several breast cancer gene expression databases revealed that G9a is a potential therapeutic target in breast cancer.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Public Library of Science (PLoS)
Date: 08-01-2020
Publisher: Public Library of Science (PLoS)
Date: 19-08-2019
Publisher: MDPI AG
Date: 25-04-2022
Abstract: Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can have cancer-promoting effects on skin cells, we performed RNA sequencing and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from four S. aureus clinical strains isolated from AK and SCC. Secretomes of two of the S. aureus strains induced keratinocytes to overexpress biomarkers associated with skin carcinogenesis and upregulated the expression of enzymes linked to reduced skin barrier function. Further, these strains induced oxidative stress markers and all secretomes downregulated DNA repair mechanisms. Subsequent experiments on an expanded set of lesion-associated S. aureus strains confirmed that exposure to their secretomes led to increased oxidative stress and DNA damage in primary human keratinocytes. A significant correlation between the concentration of S. aureus phenol soluble modulin toxins in secretome and the secretome-induced level of oxidative stress and genotoxicity in keratinocytes was observed. Taken together, these data demonstrate that secreted compounds from lesion-associated clinical isolates of S. aureus can have cancer-promoting effects in keratinocytes that may be relevant to skin oncogenesis.
Publisher: American Chemical Society (ACS)
Date: 18-02-2020
Publisher: Wiley
Date: 05-2022
DOI: 10.1002/CTM2.810
Abstract: The risk of esophageal adenocarcinoma (EAC) is associated with gastro‐esophageal reflux disease (GERD) and obesity. Lipid metabolism‐targeted therapies decrease the risk of progressing from Barrett's esophagus (BE) to EAC, but the precise lipid metabolic changes and their roles in genotoxicity during EAC development are yet to be established. Esophageal biopsies from the normal epithelium (NE), BE, and EAC, were analyzed using concurrent lipidomics and proteomics ( n = 30) followed by orthogonal validation on independent s les using RNAseq transcriptomics ( n = 22) and immunohistochemistry (IHC, n = 80). The EAC cell line FLO‐1 was treated with FADS2 selective inhibitor SC26196, and/or bile acid cocktail, followed by immunofluorescence staining for γH2AX. Metabolism‐focused Reactome analysis of the proteomics data revealed enrichment of fatty acid metabolism, ketone body metabolism, and biosynthesis of specialized pro‐resolving mediators in EAC pathogenesis. Lipidomics revealed progressive alterations (NE‐BE‐EAC) in glycerophospholipid synthesis with decreasing triglycerides and increasing phosphatidylcholine and phosphatidylethanolamine, and sphingolipid synthesis with decreasing dihydroceramide and increasing ceramides. Furthermore, a progressive increase in lipids with C20 fatty acids and polyunsaturated lipids with ≥4 double bonds were also observed. Integration with transcriptome data identified candidate enzymes for IHC validation: Δ4‐Desaturase, Sphingolipid 1 (DEGS1) which desaturates dihydroceramide to ceramide, and Δ5 and Δ6‐Desaturases (fatty acid desaturases, FADS1 and FADS2), responsible for polyunsaturation. All three enzymes showed significant increases from BE through dysplasia to EAC, but transcript levels of DEGS1 were decreased suggesting post‐translational regulation. Finally, the FADS2 selective inhibitor SC26196 significantly reduced polyunsaturated lipids with three and four double bonds and reduced bile acid‐induced DNA double‐strand breaks in FLO‐1 cells in vitro. Integrated multiomics revealed sphingolipid and phospholipid metabolism rewiring during EAC development. FADS2 inhibition and reduction of the high polyunsaturated lipids effectively protected EAC cells from bile acid‐induced DNA damage in vitro, potentially through reduced lipid peroxidation.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
DOI: 10.1007/S00216-003-2138-0
Abstract: A method for the quantitative determination of oligogalacturonic acids (OGAs) by on-line high-performance liquid chromatographic (HPLC) separation and mass spectrometric detection via an electrospray interface (ESI-MS) without additional desalting steps was developed. Saturated OGAs up to a degree of polymerization (dp) of 3 were quantified by comparison with reference compounds. The calibration plots showed high linearity (R(2)>0.99), and the detection limits for dp 1, 2, and 3 were 11, 28, and 6 ng per injection, respectively. Non- and partially methyl-esterified OGAs with a dp of 3 and 4 were calculated semi-quantitatively as dp 3. The analytical system was used for the quantification of OGAs of digests obtained by incubation of polygalacturonic acid, pectin, and carrot pomace with commercial enzyme preparations. Furthermore, methyl-esterified OGAs up to a dp of 12 containing up to 4 methyl esters were detected in a pectin digest.
Publisher: Elsevier BV
Date: 05-2019
Publisher: Public Library of Science (PLoS)
Date: 03-02-2016
Publisher: American Society for Microbiology
Date: 14-07-2023
Abstract: Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo . Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0008-6215(02)00348-8
Abstract: A method for the simultaneous determination of saturated and unsaturated oligogalacturonic acids up to degree of polymerization (dp) of 7 by high-performance liquid chromatography (HPLC) is presented. For this purpose, a Cyclobond I 2000 column and a volatile mobile phase consisting of ammonium formate and methanol were used, allowing direct coupling of HPLC to a mass spectrometer via an electrospray interface (ESI-MS) without additional desalting. The analytical system was used for the characterization of digests obtained by incubation of polygalacturonic acid with commercial enzyme preparations.
Publisher: Elsevier BV
Date: 12-2003
Publisher: Springer Science and Business Media LLC
Date: 28-07-2017
DOI: 10.1038/S41598-017-06680-4
Abstract: The cleavage preferences of Kallikrein-related peptidase 7 (KLK7) have previously been delineated using synthetic peptide libraries of fixed length, or single protein chains and have suggested that KLK7 exerts a chymotryptic-like cleavage preference. Due to the short length of the peptides utilised, only a limited number of subsites have however been assessed. To determine the subsite preferences of KLK7 in a global setting, we used a mass spectrometry (MS)-based in-depth proteomics approach that utilises human proteome-derived peptide libraries of varying length, termed Proteomic Identification of protease Cleavage Sites (PICS). Consistent with previous findings, KLK7 was found to exert chymotryptic-like cleavage preferences. KLK7 subsite preferences were also characterised in the P2-P2′ region, demonstrating a preference for hydrophobic residues in the non-prime and hydrophilic residues in the prime subsites. Interestingly, single catalytic triad mutant KLK7 (mKLK7 S195A) also showed residual catalytic activity (k cat /K M = 7.93 × 10 2 s −1 M −1 ). Catalytic inactivity of KLK7 was however achieved by additional mutation in this region (D102N). In addition to characterising the cleavage preferences of KLK7, our data thereby also suggests that the use of double catalytic triad mutants should be employed as more appropriate negative controls in future investigations of KLK7, especially when highly sensitive MS-based approaches are employed.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2018
DOI: 10.1038/S41598-018-21763-6
Abstract: Childhood maltreatment (CM) can increase the risk of adverse health consequences in adulthood. A deeper insight in underlying biological pathways would be of high clinical relevance for early detection and intervention. The untargeted investigation of all detectable metabolites and lipids in biological s les represents a promising new avenue to identify so far unknown biological pathways associated with CM. Using an untargeted approach, liquid chromatography-mass spectrometry (LC-MS) was performed on peripheral blood serum s les collected three months postpartum from 105 women with varying degrees of CM exposure. Comprehensive univariate and multivariate statistical analyses consistently identified eight biomarker candidates putatively belonging to antioxidant-, lipid-, and endocannabinoid-associated pathways, which differentiated between women with and without CM. Classification algorithms allowed for clear prediction of the CM status with high accuracy scores (~80–90%). Similar results were obtained when excluding all women with a lifetime psychiatric diagnosis. In order to confirm the identities of these promising biomarker candidates, LC-MS/MS analysis was applied, confirming one of the metabolites as bilirubin IXa, a potent antioxidant with immunomodulatory properties. In sum, our results suggest novel pathways that could explain long-term effects of CM on health and disease by influencing biological patterns associated with energy metabolism, inflammation, and oxidative stress.
Publisher: Elsevier BV
Date: 03-2017
No related grants have been discovered for Thomas Stoll.