ORCID Profile
0000-0002-5570-9645
Current Organisations
University of Wollongong
,
Organisation
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Queen Mary University of London
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Biochemistry and Cell Biology | Biochemistry And Cell Biology Not Elsewhere Classified | Enzymes | Ecology | Characterisation of Biological Macromolecules | Analytical Biochemistry | Microbiology Not Elsewhere Classified | Ecology And Evolution Not Elsewhere Classified | Biotechnology Not Elsewhere Classified | Comparative Physiology | Terrestrial Ecology | Life Histories (Incl. Population Ecology) | Structural Biology (incl. Macromolecular Modelling) |
Biological sciences | Living resources (flora and fauna) | Human Pharmaceutical Treatments (e.g. Antibiotics) | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Control of pests and exotic species | Diagnostics | Treatments (e.g. chemicals, antibiotics) | Other
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488953.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1038/MODPATHOL.2017.128
Abstract: Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.
Publisher: Elsevier BV
Date: 10-2006
Publisher: MDPI AG
Date: 14-08-2021
Abstract: Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.
Publisher: Impact Journals, LLC
Date: 18-02-2017
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
DOI: 10.1038/S41598-021-92335-4
Abstract: Perineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: Elsevier BV
Date: 05-2021
Publisher: Frontiers Media SA
Date: 02-08-2022
Abstract: Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3′ untranslated region (3′UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value & 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene lification was much less frequent, and few genes were recurrently lified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of “TGF-beta regulation of extracellular matrix” and “cell cycle G1 to S check points.” These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532844.V1
Abstract: AbstractPurpose: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. Experimental Design: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Results: Nonprogressing primary HNcSCC were characterized by higher CD8 sup + /sup and CD4 sup + /sup T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Conclusions: Effective responses from both CD8 sup + /sup and CD4 sup + /sup T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC. /
Publisher: Springer Science and Business Media LLC
Date: 27-03-2019
DOI: 10.1038/S42003-019-0361-2
Abstract: There is evidence that lower height is associated with a higher risk of coronary artery disease (CAD) and increased risk of type 2 diabetes (T2D). It is not clear though whether these associations are causal, direct or mediated by other factors. Here we show that one standard deviation higher genetically determined height (~6.5 cm) is causally associated with a 16% decrease in CAD risk (OR = 0.84, 95% CI 0.80–0.87). This causal association remains after performing sensitivity analyses relaxing pleiotropy assumptions. The causal effect of height on CAD risk is reduced by 1–3% after adjustment for potential mediators (lipids, blood pressure, glycaemic traits, body mass index, socio-economic status). In contrast, our data suggest that lung function (measured by forced expiratory volume [FEV1] and forced vital capacity [FVC]) is a mediator of the effect of height on CAD. We observe no direct causal effect of height on the risk of T2D.
Publisher: MDPI AG
Date: 09-12-2021
Abstract: Prostate cancer is a leading cause of cancer-associated deaths in men over 60 years of age. Most patients are killed by tumor metastasis. Recent evidence has implicated a role of the tumor microenvironment and urokinase plasminogen activator (uPA) in cancer cell migration, invasion, and metastasis. Here, we examine the role of the Na+/H+ exchanger isoform 1 (NHE1) and uPA in DU 145 prostate cancer cell migration and colony formation. Knockout of NHE1 reduced cell migration. The effects of a series of novel NHE1/uPA hexamethylene-amiloride-based inhibitors with varying efficacy towards NHE1 and uPA were examined on prostate cancer cells. Inhibition of NHE1—alone, or with inhibitors combining NHE1 or uPA inhibition—generally did not prevent prostate cancer cell migration. However, uPA inhibition—but not NHE1 inhibition—prevented anchorage-dependent colony formation. Application of inhibitors at concentrations that only saturate uPA inhibition decreased tumor invasion in vivo. The results suggest that while knockout of NHE1 affects cell migration, these effects are not due to NHE1-dependent proton translocation. Additionally, while neither NHE1 nor uPA activity was critical in cell migration, only uPA activity appeared to be critical in anchorage-dependent colony formation of DU 145 prostate cancer cells and invasion in vivo.
Publisher: Elsevier BV
Date: 06-2007
Publisher: Bentham Science Publishers Ltd.
Date: 2008
DOI: 10.2174/157489208783478711
Abstract: Breast cancer is the most common malignancy afflicting Western women today and is responsible for many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) has been shown to correlate with poor prognosis in metastatic breast cancer and targeting this system represents an attractive strategy for the development of anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). This review begins with a brief overview of the role of PAS in cancer metastasis before describing in detail a subset of the small molecules and peptides from the patent literature that target either uPA activity or uPA/uPAR interactions for use as anti-metastasis drugs.
Publisher: BMJ
Date: 12-07-2020
DOI: 10.1136/JCLINPATH-2019-206038
Abstract: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management. Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of in idual tumours were analysed. High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20–89) with the two patients years of age showing highest intratumour heterogeneity. TP53 was altered at VAF % in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance ( KIT S821F, KIT T670I, RAS mutations at codons 12 and 13). We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2015
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.NUCMEDBIO.2012.01.006
Abstract: Tumour-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, and it is recognised as having strong prognostic relevance as well as being a therapeutic target. The specific uPA inhibitor plasminogen activator inhibitor type-2 (PAI-2, SerpinB2) specifically targets cell bound uPA and is internalised. Furthermore, preclinical studies have established the "proof-of-principle" of uPA-targeting by PAI-2-cytotoxin conjugates in human carcinoma models. However, these studies also suggest that PAI-2 is rapidly cleared via the renal system with low total dose reaching the tumour. In this study, a comparative single photon emission computed tomography (SPECT) and biodistribution (BD) analysis of different forms of PAI-2 labelled with the radioisotopes iodine-123 ((123)I) and technetium-99m ((99m)Tc) was undertaken. The pharmacokinetic (PK) properties and BD of wild-type, ΔCD-loop and PEGylated ΔCD-loop PAI-2 labelled with the commonly used diagnostic SPECT radioisotopes (99m)Tc or (123)I were compared in mouse models of human prostate carcinoma. Whole body SPECT imaging was also performed. Both wild-type and the shorter but active ΔCD-loop form of PAI-2 (123)I-labelled indirectly via conjugation to free amine groups (termed (123)I-Bn-PAI-2) exhibited low tumour uptake, rapid excretion and similar PK profiles. Preliminary studies with a short branched-chain PEGylated (123)I-Bn-PAI-2 ΔCD-loop indicated an increase in blood retention time and tumour uptake. All (123)I-Bn-labelled radiotracers were largely excreted through the kidneys. By comparison, both wild-type (123)I-PAI-2 (labelled directly via tyrosine residues) and (99m)Tc-PAI-2 displayed different PK/BD patterns compared to (123)I-Bn-PAI-2, suggesting greater liver based catabolism and thus slower elimination. SPECT imaging mimicked the BD results of all radiotracers. The different labelling methods gave distinct PAI-2 BD and tumour uptake profiles, with radioiodination resulting in the best non-tumour organ clearance profiles. Preliminary analyses with short branched-chain PEGylated (123)I-Bn-PAI-2 ΔCD-loop suggest that further investigations with other PEGylation reagents are required to optimise this approach for tumour imaging. These findings impact on the use of PAI-2 for drug delivery and/or diagnostic development.
Publisher: Springer Science and Business Media LLC
Date: 21-05-2020
DOI: 10.1038/S41467-020-15706-X
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry ( N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2021
DOI: 10.1038/S41586-020-03065-Y
Abstract: Host-mediated lung inflammation is present
Publisher: American Chemical Society (ACS)
Date: 21-09-2007
DOI: 10.1021/JM0704189
Abstract: A range of substituted N-alkylisatins were synthesized and their cytotoxicity evaluated against several cancer cell lines in vitro. SAR studies indicated that the introduction of an aromatic ring with a one or three carbon atom linker at N1 enhanced the activity from that of the allyl, 2'-methoxyethyl, and 3'-methylbutyl N-substituted isatins. Furthermore, electron-withdrawing groups substituted at the meta or para position of the ring were favored over the ortho orientation. Of the 24 compounds screened, nine displayed sub-micromolar IC50 values and in general demonstrated greater selectivity toward leukemia and lymphoma cell lines over any of the carcinoma cell lines tested. 5,7-Dibromo-N-(p-methylbenzyl)isatin (6) was the most active compound, inhibiting the metabolic activity of both U937 and Jurkat cancer cell lines at 0.49 muM. Various N-alkylisatins were also found to dramatically alter lymphocyte morphology, destabilize microtubules, inhibit tubulin polymerization, induce G2/M cell cycle arrest, and activate the effector caspase-3 and -7.
Publisher: Wiley
Date: 08-1988
Abstract: Normal human epidermal melanocytes are attached to a basement membrane, a specialized form of extracellular matrix (ECM), located between the epithelium and underlying dermal tissues. To determine whether ECM influences pigmented cell behavior in vitro, human epidermal melanocytes and melanoma cells were cultured on uncoated or ECM-coated plastic culture surfaces, and a comparison was made between growth and function in the presence or absence of ECM. Melanocytes cultured on ECM-coated surfaces developed flatter and larger cell bodies and produced more melanin than melanocytes cultured on uncoated surfaces. In the presence of phorbol-myristate-acetate and cholera toxin, the rate of melanocyte replication was increased by ECM. In the absence of these mitogens, ECM significantly enhanced the adhesiveness of nonproliferating melanocytes. ECM had little or no effect on these parameters (morphology, tyrosinase activity, replication) in a pigmented human malignant melanoma cell line. These findings indicate that normal human epidermal pigment cells have the ability to recognize and respond to matrix signals, whereas this capacity appears to be absent in melanoma cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
Publisher: Georg Thieme Verlag KG
Date: 06-2011
Abstract: Plasminogen activator inhibitor (PAI)-2 expression is acutely upregulated in pregnancy, inflammation, infection, and other pathophysiological conditions. Circumstances that prevent PAI-2 upregulation are associated with chronic pathology. Altogether this strongly suggests that PAI-2 is one of the many proteins that maintain homeostasis during damage or stress. However, several functions ranging from a classical serpin to various intracellular roles have been ascribed to PAI-2 and, because none of these have been definitively proven in vivo, to this day its precise role or roles remains an enigma. This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2.
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1002/RTH2.12368
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41588-018-0297-3
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Publisher: MDPI AG
Date: 18-01-2022
DOI: 10.3390/BIOM12020152
Abstract: Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2021
DOI: 10.1101/2021.09.02.21262965
Abstract: Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care 1 or hospitalisation 2 4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling ( IL10RB, PLSCR1 ), leucocyte differentiation ( BCL11A ), and blood type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase ( ATP11A ), and increased mucin expression ( MUC1 ), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.PATHOL.2019.03.009
Abstract: Gastroesophageal adenocarcinoma is a common and highly lethal malignancy. Cancer stem cells (CSCs) have a key role in the development and progression of metastatic disease. While expression of CSC markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1) in locoregional gastroesophageal cancer is known to be associated with poorer clinical outcomes, the significance of CSC marker expression in distal metastatic disease is unknown. We investigated the clinicopathological and prognostic associations of the CSC markers, CD44, CD133, and ALDH1, on metastatic deposits from gastroesophageal adenocarcinomas, and evaluated the association of CSC expression with urokinase-type plasminogen activator receptor (uPAR) expression. Of the 36 patients included in the study, 16 (44%) were positive for CD44, 13 (36%) were positive for CD133, and 26 (72%) were positive for ALDH1. CD44 expression was significantly associated with poorer overall survival (OS) in univariate [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.9, p=0.008] and multivariate analyses (HR 2.5, 95%CI 1.1-6.2, p=0.04). ALDH1 expression was significantly associated with poorer OS in univariate (HR 2.4, 95% CI 1.01-5.7, p=0.04) analysis but was not significant in multivariate analysis. Both CD44 and ALDH1 expression were significantly associated with uPAR expression. We found no association between CD133 expression and OS. CD44 expression on metastatic disease from gastroesophageal adenocarcinomas is an independent prognostic marker associated with poorer OS. These results expand current evidence to support the role of CSCs as biomarkers in metastatic gastroesophageal cancer.
Publisher: Elsevier BV
Date: 02-2018
Publisher: MDPI AG
Date: 15-12-2020
DOI: 10.3390/IJMS21249536
Abstract: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2–5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease. In this study, we describe novel patient-derived cell lines from cSCC metastases of the head and neck (designated UW-CSCC1 and UW-CSCC2). The cell lines genotypically and phenotypically resembled the original patient tumor and were tumorogenic in mice. Differences in cancer-related gene expression between the tumor and cell lines after various culturing conditions could be largely reversed by xenografting and reculturing. The novel drug susceptibilities of UW-CSCC1 and an irradiated subclone UW-CSCC1-R to drugs targeting cell cycle, PI3K/AKT/mTOR, and DNA damage pathways were observed using high-throughput anti-cancer and kinase-inhibitor compound libraries, which correlate with either copy number variations, targetable mutations and/or the upregulation of gene expression. A secondary screen of top hits in all three cell lines including PIK3CA-targeting drugs supports the utility of targeting the PI3K/AKT/mTOR pathway in this disease. UW-CSCC cell lines are thus useful preclinical models for determining targetable pathways and candidate therapeutics.
Publisher: American Chemical Society (ACS)
Date: 10-05-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00142
Abstract: The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5'-substituted amiloride derivatives as hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [(3)H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([(3)H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.CLCC.2018.05.004
Abstract: Colon cancer is common in the elderly, but owing to under representation in clinical trials, the benefit of standard therapies is uncertain in this age group. We aimed to clarify the efficacy and complications of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for patients 70 years and older with stage III colon cancer. All patients with stage III colon adenocarcinoma were identified from an Australian cancer registry (2006-2013). Multivariable Cox hazard regression was used to determine prognostic factors for all-cause mortality. Chemotherapy complications were quantified using discontinuation rates, hospital admissions, and mortality for 12 months after starting chemotherapy. A total of 2164 patients fulfilled our inclusion criteria, including 1080 (49.9%) patients ≥ 70 years. Patients ≥ 70 years were less likely to receive adjuvant chemotherapy (60.7% vs. 89.6%) or oxaliplatin doublet chemotherapy (18.8% vs. 71.2%). Older patients receiving oxaliplatin were more likely to cease treatment early (18.7% vs. 7.6%) and require hospital admission (67.0% vs. 53.5%). The addition of oxaliplatin provided an overall survival benefit for patients < 70 years (hazard ratio, 0.44 95% confidence interval, 0.3-0.6 P < .0001) and for patients ≥ 70 years (hazard ratio, 0.64 95% confidence interval, 0.5-0.9 P = .005). Despite a modestly increased rate of hospital admission and early chemotherapy cessation, we demonstrate a persistent survival benefit for the addition of oxaliplatin to a fluoropyrimidine as adjuvant treatment for stage III colon cancer in elderly patients.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488959.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.BMCL.2010.03.029
Abstract: A urokinase targeting conjugate of 2'-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2'-deoxy-5-fluoro-3'-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile succinate linker was attached to the specific urokinase inhibitor plasminogen activator inhibitor type II (PAI-2) and was found to preferentially kill urokinase-over expressing cancer cells. Up to 7 molecules of 5-FUdr were incorporated per PAI-2 molecule without affecting protein activity. This is the first time a small organic cytotoxin has been conjugated to PAI-2.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488950
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Oxford University Press (OUP)
Date: 30-07-2021
DOI: 10.1093/BIB/BBAB259
Abstract: Significant innovations in next-generation sequencing techniques and bioinformatics tools have impacted our appreciation and understanding of RNA. Practical RNA sequencing (RNA-Seq) applications have evolved in conjunction with sequence technology and bioinformatic tools advances. In most projects, bulk RNA-Seq data is used to measure gene expression patterns, isoform expression, alternative splicing and single-nucleotide polymorphisms. However, RNA-Seq holds far more hidden biological information including details of copy number alteration, microbial contamination, transposable elements, cell type (deconvolution) and the presence of neoantigens. Recent novel and advanced bioinformatic algorithms developed the capacity to retrieve this information from bulk RNA-Seq data, thus broadening its scope. The focus of this review is to comprehend the emerging bulk RNA-Seq-based analyses, emphasizing less familiar and underused applications. In doing so, we highlight the power of bulk RNA-Seq in providing biological insights.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BMC.2011.01.015
Abstract: In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para-phenylpropionic acid>phenylacetic acid (para>meta)>benzoic acid (meta>para). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugates.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488953
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 18-02-2019
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/272148
Abstract: Multiple species of bacteria are able to sequester the host zymogen plasminogen to the cell surface. Once localised to the bacterial surface, plasminogen can act as a cofactor in adhesion, or, following activation to plasmin, provide a source of potent proteolytic activity. Numerous bacterial plasminogen receptors have been identified, and the mechanisms by which they interact with plasminogen are erse. Here we provide an overview of bacterial plasminogen receptors and discuss the erse role bacterial plasminogen acquisition plays in the relationship between bacteria and the host.
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488947
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BMCL.2016.02.033
Abstract: Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that non-indoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of non-indoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.
Publisher: Research Square Platform LLC
Date: 10-03-2022
DOI: 10.21203/RS.3.RS-1409164/V1
Abstract: Hypertension is a leading cause of premature death affecting more than a billion in iduals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent in iduals). We identified 2,103 independent genetic signals (P 5x10 − 8 ) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10 − 73 ) and hypertension risk (OR 5.41 95% CI 4.12 to 7.10 P = 9.71×10 − 33 ) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10 − 22 ). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
Publisher: MDPI AG
Date: 24-08-2020
Abstract: Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by αv overexpression or abolished by excess vitronectin, anti-αv antibodies or silencing of ITGAV αv gene, identifying αv-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for αv integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced α-smooth muscle actin (α-SMA) levels. Finally, peptide exposure of αv-expressing primary CAFs led to the downregulation of α-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.
Publisher: IOP Publishing
Date: 05-11-2020
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JID.2019.01.008
Abstract: Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTC-binding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Elsevier BV
Date: 10-1995
Abstract: Gnot1, a Not (for notochord) family homeobox gene, is expressed in the chick pregastrulation blastoderm. Gnot1 expression in the epiblast is upregulated as the posteriorly derived hypoblast moves forward anteriorly to form a layer beneath it, which is of particular interest considering the known inductive role of the hypoblast in axis formation in the chick. Both activin and retinoic acid are able to activate Gnot1 expression in cultured blastodermal cells and show a strong synergistic effect when applied in combination. Strong superinduction of Gnot1 transcripts in the presence of cycloheximide also indicates the presence of a potent and labile intracellular inhibitor capable of modulating Gnot1 expression. During gastrulation, Gnot1 transcripts become localized specifically to tissues associated with "organizer" function (Hensen's node, head process, notochord). The expression data and the response to mesoderm inducing factors and axial "caudalizing" signals suggest that Gnot1 may be involved in specification of the embryonic body axis and could play a part in regulating features of the trunk/tail organizer in the chick embryo.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.BMCL.2011.09.044
Abstract: A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K(i)=7 μM), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Elsevier BV
Date: 04-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2011
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 14-05-2009
Abstract: Plasminogen activator inhibitor type-2 (PAI-2, SERPINB2) is an irreversible, specific inhibitor of the urokinase plasminogen activator (uPA). Since overexpression of uPA at the surface of cancer cells is linked to malignancy, targeting of uPA by exogenous recombinant PAI-2 has been proposed as the basis of potential cancer therapies. To this end, reproducible yields of high purity protein that maintains this targeting ability is required. Herein we validate the use in vitro of recombinant 6 × His-tagged-PAI-2 lacking the intrahelical loop between C and D alpha-helices (PAI-2 ΔCD-loop) for these purposes. We show that PAI-2 ΔCD-loop expressed and purified from the pQE9 vector system presents an easier purification target than the previously used pET15b system. Additionally, PAI-2 ΔCD-loop gave both higher yield and purity than wild-type PAI-2 expressed and purified under identical conditions. Importantly, absence of the CD-loop had no impact on the inhibition of both solution phase and cell surface uPA or on the clearance of receptor bound uPA from the cell surface. Furthermore, uPA:PAI-2 ΔCD-loop complexes had similar binding kinetics (K D ~5 nM) with the endocytosis receptor Very Low Density Lipoprotein Receptor (VLDLR) to that previously published for uPA:PAI-2 complexes. We demonstrate that the CD-loop is redundant for the purposes of cellular uPA inhibition and cell surface clearance (endocytosis) and is thus suitable for the development of anti-uPA targeted cancer therapeutics.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.ENVPOL.2009.05.005
Abstract: The role of vegetation in mitigating the effects of PM(10) pollution has been highlighted as one potential benefit of urban greenspace. An integrated modelling approach is presented which utilises air dispersion (ADMS-Urban) and particulate interception (UFORE) to predict the PM(10) concentrations both before and after greenspace establishment, using a 10 x 10 km area of East London Green Grid (ELGG) as a case study. The corresponding health benefits, in terms of premature mortality and respiratory hospital admissions, as a result of the reduced exposure of the local population are also modelled. PM(10) capture from the scenario comprising 75% grassland, 20% sycamore maple (Acer pseudoplatanus L.) and 5% Douglas fir (Pseudotsuga menziesii (Mirb.) Franco) was estimated to be 90.41 t yr(-1), equating to 0.009 t ha(-1) yr(-1) over the whole study area. The human health modelling estimated that 2 deaths and 2 hospital admissions would be averted per year.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.BIOCEL.2016.08.018
Abstract: Pregnancy zone protein (PZP) and plasminogen activator inhibitor type 2 (PAI-2) are two multifunctional proteins that are elevated in normal pregnancy and numerous other inflammatory states. Both proteins were originally identified as protease inhibitors, but current evidence supports the notion that they may also function as modulators of T-helper cells and/or extracellular chaperones. Exacerbated inflammation, fibrinolytic disturbances and misfolded proteins are all implicated in the pathology of preecl sia, a leading cause of maternal and foetal mortality and morbidity. Notably, reduced levels of PZP or PAI-2 are associated with preecl sia and clarification of their erse functions in normal pregnancy could provide much needed insight regarding the pathogenesis of this disorder. Given that inflammation and protein misfolding underlie the pathology of a very large number of disorders, the contributions of PZP and PAI-2 to extracellular proteostasis and immunoregulation could be broad-reaching.
Publisher: MDPI AG
Date: 15-03-2021
DOI: 10.3390/IJMS22062999
Abstract: The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.PATHOL.2017.04.004
Abstract: Programmed cell death (PD-1) and its ligand (PD-L1) inhibitors have shown clinical response in many tumours. PD-L1 data are limited in head and neck cutaneous squamous cell carcinoma (HNcSCC) and no clinical trials of PD-1/PD-L1 inhibitors are published. We performed PD-L1 immunohistochemistry on 74 cases of high risk HNcSCC with 38 matched metastases and evaluated clinicopathological associations, prognostic significance and heterogeneity in matched metastases. We observed PD-L1 expression in >5% of primary tumour cells in 29 cases (39.2%), primary tumour infiltrating lymphocytes (TILs) in 40 cases (70.2%), metastatic tumour cells in 15 cases (39.5%), and metastatic TILs in 18 cases (47.4%). PD-L1 expression in >5% of primary tumour cells was associated with an inflammatory phenotype (p = 0.04), and in primary TILs with clear margins (p = 0.05). PD-L1 expression in >5% of primary tumour cells (p = 0.01), primary TILs (p = 0.001), and metastatic TILs (p = 0.02) was associated with improved disease free survival. PD-L1 expression in >5% of tumour cells was heterogeneous between primary and metastatic tumours in 13 cases (34.2%). PD-L1 expression is common in HNcSCC supporting the rationale for a clinical trial of PD-1/PD-L1 inhibitors. PD-L1 expression in tumour cells or TILs predicts longer disease free survival and demonstrates temperospatial heterogeneity.
Publisher: Wiley
Date: 08-2020
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.PATHOL.2017.04.002
Abstract: Head and neck cutaneous squamous cell carcinoma (HNcSCC) can present with cervical metastases without an obvious primary. Immunohistochemistry for p16 is established as a surrogate marker of human papillomavirus (HPV) in oropharyngeal cancer. p16 expression in HNcSCC needs to be elucidated to determine its utility in predicting the primary site. The aim of this study was to evaluate the rate of p16 expression in HNcSCC and its association with prognostic factors and survival. p16 immunohistochemistry was performed on 166 patients with high risk HNcSCC (2000-2013) following histopathology review. Chromogenic in situ hybridisation (CISH) for HPV was performed. Fifty-three (31.9%) cases showed strong, diffuse nuclear and cytoplasmic p16 expression including 14 (41%) non-metastatic and 39 (29.5%) metastatic tumours (p=0.21). HPV CISH was negative in all cases. p16 expression significantly increased with poorer differentiation (p=0.033), but was not associated with size (p=0.30), depth of invasion (p=0.94), lymphovascular invasion (p=0.31), perineural invasion (p=0.69), keratinisation (p=0.99), number of involved nodes (p=0.64), extranodal extension (p=0.59) or survival. Nearly 32% of HNcSCCs, particularly poorly differentiated HNcSCCs, show p16 expression. A primary HNcSCC should be considered in p16 positive neck node metastases in regions with high prevalence of HNcSCC. p16 expression is not associated with improved survival in HNcSCC.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2010
Publisher: MDPI AG
Date: 29-03-2022
Abstract: Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preecl sia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preecl sia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preecl tic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preecl sia.
Publisher: American Society for Microbiology
Date: 08-2003
DOI: 10.1128/IAI.71.8.4823-4827.2003
Abstract: Mycoplasma species bovine group 7 bound plasminogen at the cell surface in a lysine-dependent manner. Cell-bound plasminogen was rapidly activated to plasmin by exogenous urokinase, and this activity was associated with plasminogen binding capacity. Binding assays using plasminogen modified with a trifunctional cross-linking agent revealed several binding proteins.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NG.3014
Publisher: Public Library of Science (PLoS)
Date: 04-07-2013
Publisher: Springer Science and Business Media LLC
Date: 28-01-2007
DOI: 10.1186/BCR1647
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: Metastasis is the principal cause of death in breast cancer patients. New and improved treatments for eradicating micrometastases are needed. To this end, a novel alpha-emitting protein construct, 213Bi-labelled plasminogen activator inhibitor type-2 (PAI-2) (alpha-PAI-2), was evaluated in vitro. This construct exploits: (a) the overexpression of the cell-surface receptor bound urokinase plasminogen activator (uPA) in the metastatic spread of breast cancer cells (b) the binding and inhibition of receptor-bound uPA by PAI-2 and (c) the high cytotoxicity of alpha radiation. High labeling efficiencies and stability of 213Bi bound to human recombinant PAI-2 conjugated with cyclic diethylenetriaminepentaacetic acid anhydride were achieved (greater than 90%). The uPA inhibitory activity of the chelated PAI-2 was maintained as determined by complex formation with uPA and by inhibition of uPA activity. Furthermore, the reactivity of alpha-PAI-2 was confirmed in a cell assay as this construct was highly cytotoxic to breast cancer cell lines that express active, receptor bound uPA. The specificity of alpha-PAI-2 targeting was shown using several controls. Firstly, an active uPA blocking agent that limits PAI-2 binding significantly improved cell survival by a factor greater than three. Secondly, a non-specific alpha-BSA construct had minimal cytotoxic effect. Moreover, alpha-PAI-2 was not cytotoxic to freshly isolated normal human leukocytes, confirming that cells which do not contain active, receptor bound uPA cannot be targeted by alpha-PAI-2. In conclusion, we have validated, in vitro, the potential of alpha-PAI-2 as a novel therapeutic agent for breast cancer.
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0167-4838(96)00146-X
Abstract: Plasminogen binds with low affinity in a lysine-dependent manner to many cell types. Previously, a 54 kDa plasminogen receptor found on the surface of U-937 cells was identified as an alpha-enolase-like molecule. The aims of this study were to determine whether recombinant alpha-enolase (r-alpha-enolase), encoded by ENO1, was a plasminogen binding protein and to generate polyclonal antibodies against this antigen. Plasminogen specifically bound r-alpha-enolase with a Kd 1.9 microM and approached saturation at 10 microM. Lysine-dependent plasminogen binding to r-alpha-enolase was demonstrated by a greater than 80% inhibition of binding by the lysine analogues epsilon-amino caproic acid and tranexamic acid, whilst only 14% inhibition occurred with the arginine analogue benzamidine. Removal of the C-terminal lysine residue of r-alpha-enolase with carboxy-peptidase B significantly reduced its plasminogen binding capacity, suggesting that binding required C-terminal lysine residue of r-alpha-enolase. Binding to r-alpha-enolase enhanced the activation rate of plasminogen by urokinase but prevented alpha 2-antiplasmin from binding plasminogen. Taken together, these data suggest that the gene product of human ENO1 encodes an authentic plasminogen binding protein.
Publisher: Wiley
Date: 06-03-2019
DOI: 10.1111/AJCO.13144
Abstract: 5-Fluorouracil (5-FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all-in-one, pH neutral stable solution of 5-FU plus LV with β-cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first-in-human phase I trial. Patients with advanced solid malignancy received Deflexifol as weekly bolus (375-575 mg/m²) or two-weekly 46 h infusion (1200-3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose-limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5-FU and LV. A phase II study evaluating Deflexifol is planned.
Publisher: Impact Journals, LLC
Date: 11-06-2016
Publisher: Elsevier BV
Date: 15-03-2008
DOI: 10.1016/J.BMC.2007.12.026
Abstract: A range of N-phenethyl, N-phenacyl, and N-(1- and 2-naphthylmethyl) derivatives of 5,7-dibromoisatin 2 were prepared by N-alkylation reactions. Their activity against human monocyte-like histiocytic lymphoma (U937), leukemia (Jurkat), and breast carcinoma (MDA-MB-231) cell lines was assessed. The results allowed further development of structure-activity relationships. The compound 5,7-dibromo-N-(1-naphthylmethyl)-1H-indole-2,3-dione 5a was the most potent against U937 cells with an IC(50) value of 0.19 microM.
Publisher: Cold Spring Harbor Laboratory
Date: 14-03-2022
DOI: 10.1101/2022.03.12.484055
Abstract: Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K + -sparing diuretic amiloride is a moderate non-specific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch-cl protocol and identified 6-iodoamiloride as a more potent ASIC1 inhibitor. Follow-up IC 50 determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 97 (hASIC1 97 IC 50 88 nM cf. amiloride 11 IC 50 1.7 μM). A similar improvement in activity was observed in ASIC3-mediated currents from rat small diameter dorsal root ganglion neurons (rDRG single-concentration 97 IC 50 230 nM cf. 11 IC 50 2.7 μM). 6-iodoamiloride represents the amiloride analogue of choice for studying the effects of ASIC inhibition on cell physiology.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2008
DOI: 10.1038/NG.140
Publisher: Public Library of Science (PLoS)
Date: 07-10-2008
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.BMC.2011.03.016
Abstract: Binding of the urokinase-type plasminogen activator (uPA) to its cell-surface-bound receptor uPAR and upregulation of the plasminogen activation system (PAS) correlates with increased metastasis and poor prognosis in several tumour types. Disruptors of the uPA:uPAR interaction represent promising anti-tumour/metastasis agents and several approaches have been explored for this purpose, including the use of small molecule antagonists. Two highly potent non-peptidic antagonists 1 and 2 (IC(50)1=0.8 nM, IC(50)2=33 nM) from the patent literature were reportedly identified using competition assays employing radiolabelled uPAR-binding uPA fragments and appeared as useful pharmacological tools for studying the PAS. Before proceeding to such studies, confirmation was sought that 1 and 2 retained their potencies in physiologically relevant cell-based competition assays employing uPAR's native binding partner high molecular weight uPA (HMW-uPA). This study describes a new solution phase synthesis of 1, a mixed solid/solution phase synthesis of 2 and reports the activities of 1 and 2 in semi-quantitative competition flow cytometry assays and quantitative cell-based uPA activity assays that employed HMW-uPA as the competing ligand. The flow cytometry experiments revealed that high concentrations of 2 (10-100 μM) are required to compete with HMW-uPA for uPAR binding and that 1 shows no antagonist effects at 100 μM. The cell-based enzyme activity assays similarly revealed that 1 and 2 are poor inhibitors of cell surface-bound HMW-uPA activity (IC(50) >100 μM for 1 and 2). The report highlights the dangers of identifying false-positive lead uPAR antagonists from competition assays employing labelled competing ligands other than the native HMW-uPA.
Publisher: American Chemical Society (ACS)
Date: 13-12-2021
DOI: 10.1021/ACS.JMEDCHEM.1C01423
Abstract: The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising antimetastasis target. 6-Substituted analogues of 5-
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488956
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488959
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-12-2021
Abstract: Neuroserpin preferentially inhibits amyloid formation a 14-mer region in neuroserpin is implicated in binding to amyloid.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
DOI: 10.1161/HYPERTENSIONAHA.117.09438
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry in iduals and sought significant evidence for independent replication in a further 228 245 in iduals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Publisher: Wiley
Date: 21-06-2006
Abstract: The globally disseminated Streptococcus pyogenes M1T1 clone causes a number of highly invasive human diseases. The transition from local to systemic infection occurs by an unknown mechanism however invasive M1T1 clinical isolates are known to express significantly less cysteine protease SpeB than M1T1 isolates from local infections. Here, we show that in comparison to the M1T1 strain 5448, the isogenic mutant delta speB accumulated 75-fold more human plasmin activity on the bacterial surface following incubation in human plasma. Human plasminogen was an absolute requirement for M1T1 strain 5448 virulence following subcutaneous (s.c.) infection of humanized plasminogen transgenic mice. S. pyogenes M1T1 isolates from the blood of infected humanized plasminogen transgenic mice expressed reduced levels of SpeB in comparison with the parental 5448 used as inoculum. We propose that the human plasminogen system plays a critical role in group A streptococcal M1T1 systemic disease initiation. SpeB is required for S. pyogenes M1T1 survival at the site of local infection, however, SpeB also disrupts the interaction of S. pyogenes M1T1 with the human plasminogen activation system. Loss of SpeB activity in a subpopulation of S. pyogenes M1T1 at the site of infection results in accumulation of surface plasmin activity thus triggering systemic spread.
Publisher: Elsevier BV
Date: 10-2006
Publisher: Elsevier BV
Date: 08-2023
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Springer Science and Business Media LLC
Date: 18-09-2014
DOI: 10.1007/S11095-014-1517-X
Abstract: Overexpression of the serine protease urokinase (uPA) is recognised as an important biomarker of metastatic disease and a druggable anticancer target. Plasminogen activator inhibitor type-2 (PAI-2/SerpinB2) is a specific uPA inhibitor with proven potential for use in targeted therapy. However, PAI-2 is rapidly cleared via the renal system which impairs tumor uptake and efficacy. Here we aimed to improve the pharmacological properties of PAI-2 by site-specific PEGylation. Several cysteine to serine substitution mutants were generated for PEGylation with PEG-maleimide (size range 12-30 kDa) and the physico-chemical and biochemical properties of the PEG-PAI-2 conjugates characterised. Radiolabeled proteins were used for evaluation of blood clearance and tissue uptake profiles in an orthotopic breast tumor xenograft mouse model. PEGylation of the PAI-2(C161S) mutant gave a predominant mono-PEGylated-PAI-2 product (~90%) with full uPA inhibitory activity, despite a significant increase in hydrodynamic radius. Compared to un-PEGylated protein the plasma half-life and AUC for PEG20-PAI-2(C161S) were significantly increased. This translated to a 10-fold increase in tumor retention after 24 h compared to PAI-2(C161S), an effect not seen in non-target organs. Our data underscores the potential for PEG20-PAI-2(C161S) drug conjugates to be further developed as anti-uPA targeted therapeutics with enhanced tumor retention.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JCONREL.2018.03.022
Abstract: Despite the longstanding existence of liposome technology in drug delivery applications, there have been no ligand-directed liposome formulations approved for clinical use to date. This lack of translation is due to several factors, one of which is the absence of molecular tools for the robust quantification of ligand density on the surface of liposomes. We report here for the first time the quantification of proteins attached to the surface of small unilamellar liposomes using single-molecule fluorescence imaging. Liposomes were surface-functionalized with fluorescently labeled human proteins previously validated to target the cancer cell surface biomarkers plasminogen activator inhibitor-2 (PAI-2) and trastuzumab (TZ, Herceptin®). These protein-conjugated liposomes were visualized using a custom-built wide-field fluorescence microscope with single-molecule sensitivity. By counting the photobleaching steps of the fluorescently labeled proteins, we calculated the number of attached proteins per liposome, which was 11 ± 4 proteins for single-ligand liposomes. Imaging of dual-ligand liposomes revealed stoichiometries of the two attached proteins in accordance with the molar ratios of protein added during preparation. Preparation of PAI-2/TZ dual-ligand liposomes via two different methods revealed that the post-insertion method generated liposomes with a more equal representation of the two differently sized proteins, demonstrating the ability of this preparation method to enable better control of liposome protein densities. We conclude that the single-molecule imaging method presented here is an accurate and reliable quantification tool for determining ligand density and stoichiometry on the surface of liposomes. This method has the potential to allow for comprehensive characterization of novel ligand-directed liposomes that should facilitate the translation of these nanotherapies through to the clinic.
Publisher: Oxford University Press (OUP)
Date: 04-06-2013
DOI: 10.1093/HMG/DDT177
Publisher: Impact Journals, LLC
Date: 23-03-2015
Abstract: Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co- lification and/or mRNA rotein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.BBAGEN.2010.07.001
Abstract: The extracellular ATP-gated cation channel, P2X7 receptor, has an emerging role in neoplasia, however progress in the field is limited by a lack of malignant cell lines expressing this receptor. Immunofluorescence labelling and a fixed-time ATP-induced ethidium+ uptake assay were used to screen a panel of human malignant cell lines for the presence of functional P2X7. The presence of P2X7 was confirmed by RT-PCR, immunoblotting and pharmacological approaches. ATP-induced cell death was measured by colourimetric tetrazolium-based and cytofluorometric assays. ATP-induced CD23 shedding was measured by immunofluorescence labelling and ELISA. RPMI 8226 multiple myeloma cells expressed P2X7 mRNA and protein, as well as P2X1, P2X4 and P2X5 mRNA. ATP induced ethidium+ uptake into these cells with an EC₅₀ of ~116 μM, and this uptake was reduced in the presence of extracellular Ca²+ and Mg²+. The P2X7 agonist 2'- and 3'-0(4-benzoylbenzoyl) ATP, but not UTP, induced ethidium+ uptake. ATP-induced ethidium+ uptake was impaired by the P2X7 antagonists, KN-62 and A-438079. ATP induced death and CD23 shedding in RPMI 8226 cells, and both processes were impaired by P2X7 antagonists. The metalloprotease antagonists, BB-94 and GM6001, impaired ATP-induced CD23 shedding but not ethidium+ uptake. P2X7 receptor activation induces cell death and CD23 shedding in RPMI 8226 cells. RPMI 8226 cells may be useful to study the role of P2X7 in multiple myeloma and B-lymphocytes.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: IMR Press
Date: 2003
DOI: 10.2741/1044
Abstract: The urokinase plasminogen activation system is a key modulator of the tissue remodeling processes required for tumor cell invasion and metastasis. Malignant progression is characterised by inappropriately high cell surface levels of receptor- bound active urokinase. This enhances the rate of plasminogen activation resulting in markedly increased levels of cell surface plasmin. The repercussions of this are significant and include the activation of growth factors and signaling pathways, and the degradation of extracellular matrices, either directly or indirectly, via the activation of matrix metalloproteinases. Native, circulating plasminogen binds in a lysine- and/or carbohydrate-dependent manner to tumor and endothelial cells with low affinity but high capacity and a heterogeneous group of plasminogen receptors have been identified. This heterogeneity underscores the complexity of the mechanisms responsible for the regulation of cell-surface plasminogen binding. This review summarizes the literature on known plasminogen receptor candidates and shows that they can be sub ided into three classes based on their mode of interaction with plasminogen. We also aim to emphasize the notion that in the tumor environment the known intrinsic functional relationship between plasminogen conformation and activation is essentially connected to cellular binding. This allows plasminogen to be co-localised in an activation-susceptible form with the enhanced uPA levels seen in malignancy and together furnishes tumor cells with elevated tissue remodeling capacity. In addition, some of the pitfalls and strategies encountered when conducting plasminogen receptor experiments are also addressed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
DOI: 10.1161/HYPERTENSIONAHA.111.181990
Abstract: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73] combined P =2.58 · 10 −13 ). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44 P =1.032 · 10 −14 ). The quantitative analysis on a population-based s le revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2017
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.BMC.2006.10.035
Abstract: A range of substituted 1H-indole-2,3-diones (isatins) were synthesized using standard procedures and their cytotoxicity evaluated against the human monocyte-like histiocytic lymphoma (U937) cell line in vitro. SAR studies identified C(5), C(6), and C(7) substitution greatly enhanced activity with some di- and tri-halogenated isatins giving IC(50) values <10 microM. Of the 23 compounds tested, four were selected for further screening against a panel of five human cancer cell lines. These compounds, in general, showed greater selectivity toward leukemia and lymphoma cells over breast, prostate, and colorectal carcinoma cell lines. The most active compound, 5,6,7-tribromoisatin (2p), was found to be antiproliferative at low micromolar concentrations and also activated the effector caspases 3 and 7 in a dose-dependent manner. These results indicate that di- and tri-substituted isatins may be useful leads for anticancer drug development in the future.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2008
DOI: 10.1038/NG.287
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488950.V1
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 06-01-2022
Publisher: American Society for Microbiology
Date: 2004
DOI: 10.1128/IAI.72.1.364-370.2004
Abstract: Reports of resurgence in invasive group A streptococcal (GAS) infections come mainly from affluent populations with infrequent exposure to GAS. In the Northern Territory (NT) of Australia, high incidence of invasive GAS disease is secondary to endemic skin infection, serotype M1 clones are rare in invasive infection, the ersity and level of exposure to GAS strains are high, and no particular strains dominate. Expression of a plasminogen-binding GAS M-like protein (PAM) has been associated with skin infection in isolates elsewhere (D. Bessen, C. M. Sotir, T. M. Readdy, and S. K. Hollingshead, J. Infect. Dis. 173: 896-900, 1996), and subversion of the host plasminogen system by GAS is thought to contribute to invasion in animal models. Here, we describe the relationship between plasminogen-binding capacity of GAS isolates, PAM genotype, and invasive capacity in 29 GAS isolates belonging to 25 distinct strains from the NT. In the presence of fibrinogen and streptokinase, invasive isolates bound more plasminogen than isolates from uncomplicated infections ( P ≤ 0.004). Only PAM-positive isolates bound substantial levels of plasminogen by a fibrinogen-streptokinase-independent pathway (direct binding). Despite considerable amino acid sequence variation within the A1 repeat region of PAM where the plasminogen-binding domain maps, the critical lysine residue was conserved.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2020
DOI: 10.1038/S41598-019-57164-6
Abstract: Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an EpCAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM−, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term CTC cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets.
Publisher: Georg Thieme Verlag KG
Date: 2008
DOI: 10.1160/TH08-02-0119
Abstract: Regulation of cellular plasminogen activation is necessary for maintenance of tissue homeostasis. Despite increasing evidence for co-expression of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type-2 (PAI-2 SERPINB2) under patho hysiological conditions, the inhibition of cell-bound tPAmediated plasminogen activation by PAI-2 has not been addressed. Here we show that PAI-2 can inhibit cell-bound tPA activity in vitro and thus prevent plasmin formation. We also examined the potential involvement in this inhibition of the annexin II heterotetramer (AIIt), one of the many well characterized cell-surface co/receptors for tPA and plasminogen that efficiently promotes plasminogen activation. This receptor was of interest because AIIt has also been shown to directly bind PAI-2. Characterization of these potential interactions using purified protein systems revealed that PAI-2 directly bound AIIt via the p11 (S100A10) subunit. However, PAI-2 prevented AIIt/tPA-mediated plasminogen activation by its classic serpin inhibitory activity rather than through competition with tPA lasminogen for binding. Further analysis showed that PAI-2 inhibited cell bound tPA-induced plasmin activity in both an AIIt-dependent and -independent manner. These data open new possibilities for further investigations regarding the regulation of cellular plasmin generation in vivo, especially in tissues where PAI-2 and tPA may be co-expressed.
Publisher: Portland Press Ltd.
Date: 14-11-2007
DOI: 10.1042/BJ20070767
Abstract: PAI-1 and PAI-2 (plasminogen-activator inibitor types 1 and 2) are inhibitors of cell surface uPA (urokinase plasminogen activator). However, tumour expression of PAI-1 and PAI-2 correlates with poor compared with good patient prognosis in breast cancer respectively. This biological ergence may be related to additional functional roles of PAI-1. For ex le, the inhibition of uPA by PAI-1 reveals a cryptic high-affinity site within the PAI-1 moiety for the VLDLr (very-low-density-lipoprotein receptor), which sustains cell signalling events initiated by binding of uPA to its receptor. These interactions and subsequent signalling events promote proliferation of breast cancer cells. Biochemical and structural analyses show that, unlike PAI-1, the PAI-2 moiety of uPA–PAI-2 does not contain a high-affinity-binding site for VLDLr, although uPA–PAI-2 is still efficiently endocytosed via this receptor in breast cancer cells. Furthermore, global protein tyrosine phosphorylation events were not sustained by uPA–PAI-2 and cell proliferation was not affected. We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr.
Publisher: Elsevier BV
Date: 09-2006
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0960-0760(94)90295-X
Abstract: Subjects with elevated serum estrogen concentrations, such as those who are pregnant or ingesting estrogen-containing contraceptive medication, may develop increased skin pigmentation. As little information is available on the mechanism(s) underlying this relationship, the in vitro effects of estrogens on melanocytes cultured from normal human skin were examined. Physiological concentrations of 17 beta-estradiol (10(-11) to 10(-9) M) significantly increased the activity of tyrosinase in melanocytes from 15 of 23 subjects. The observed increases ranged from 1.2- to 2.4-fold. Melanin synthesis, which correlated with tyrosinase activity (r = 0.98, P < 0.001) was increased to a similar extent. Melanin extrusion was also increased by 17 beta-estradiol (10(-9) M). The estrogens, estriol (10(-9) M) and estrone (10(-9) M) stimulated tyrosinase activity and melanin extrusion to a lesser extent than 17 beta-estradiol. The analogue 17 alpha-estradiol (10(-9) M) was shown to have effects on melanocyte tyrosinase activity and melanin extrusion that were equivalent to those of 17 beta-estradiol. The pure estrogen antagonist ICI 164384 (10(-6) M) also stimulated tyrosinase activity. Cycloheximide (50 micrograms/ml) inhibited 17 beta-estradiol-induced tyrosinase stimulation (P < 0.001). These results indicate that several aspects of melanocyte function respond directly to estrogenic stimulation. The equivalent effects of the 17 alpha-analogue and a "pure" anti-estrogen suggest that the 17 beta-estradiol response may be mediated through a non-classical mechanism which is similar to that described in other tissues of neural crest origin.
Publisher: MDPI AG
Date: 23-11-2022
Abstract: Brain metastasis from gastroesophageal adenocarcinomas (GOCs) is a rare but a devastating diagnosis. Human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker in GOCs. The association of HER2 with GOC brain metastasis is not known. We performed a retrospective analysis of patients with GOCs with known HER2 status between January 2015 and November 2021. HER2 was assessed on either the primary tumour or metastasis by immunohistochemistry or in situ hybridization. The diagnosis of brain metastasis was made on standard imaging techniques in patients with symptoms or signs. HER2 results were available for 201 patients, with 34 patients (16.9%) HER2 positive. A total of 12 patients developed symptomatic brain metastasis from GOCs, of which 7 (58.3%) were HER2 positive. The development of symptomatic brain metastasis was significantly higher in the HER2-positive GOCs (OR8.26, 95%CI 2.09–35.60 p = 0.0009). There was no significant association of HER2 status and overall survival in patients with brain metastasis. Although the rate of brain metastasis remains low in GOCs, the incidence of symptomatic brain metastasis was significantly higher in patients with HER2-positive tumours.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 09-2001
Publisher: Georg Thieme Verlag KG
Date: 2010
DOI: 10.1160/TH10-02-0121
Abstract: Generation of the broad spectrum protease plasmin is facilitated by the tissue (t-PA) and urokinase (u-PA) plasminogen activators, within multiple physiological and disease states. Finely tuned control of this proteolytic cascade is exerted by the plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and 2 (PAI-2/SERPINB2). Expression of this network of activators and inhibitors by cells of myeloid lineage appears to be highly interchangeable between physiological environments, and whilst the role of PAI-1 and PAI-2 in regulating u-PA-dependent functions is well established, the interaction between t-PA and PAI-2 on these cell types is poorly characterised. To this end, we used freshly isolated peripheral blood monocytes (PBM) as a model of a t-PA-dependent cellular environment. We demonstrate that while both PAI-1 and PAI-2 could inhibit surface-bound t-PA and are internalised predominately via low-density-lipoprotein receptor family members, PAI-1 enhanced the endocytosis of t-PA, whereas PAI-2 did not. Surface plasmon resonance analyses revealed differential binding affinities between the very-low-density-lipoprotein receptor and t-PA and t-PA:PAI-1 complexes in addition to those previously described with low-density-lipoprotein receptor-related protein. Moreover, t-PA:PAI-2 bound to both endocytosis receptors with similar kinetics to t-PA. These differential biochemical interactions between t-PA and the t-PA:PAI complexes may underlie the observed differences in endocytosis mechanisms on the PBMs. This suggests that while PAI-1 and PAI-2 function similarly in the control of cellular plasmin generation by t-PA, they may have disparate effects on the alternative functions of t-PA via modulation of its engagement with endocytosis receptors.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 03-2003
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488956.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.CANLET.2011.10.021
Abstract: We have previously reported a series of pH-sensitive imine-linked N-alkylisatin prodrugs that are stable at pH 7.4, but readily cleaved at pH 4.5. Herein, one of the most potent prodrugs, 5,7-dibromo-N-(p-methoxybenzyl)isatin (NAI), was functionalized with a para-phenylpropionic acid linker, and the resulting NAI-imine prodrug conjugated to transferrin (Tf) to form a NAI-imine-Tf conjugate. Cytotoxicity assays revealed the conjugate was equipotent to the free drug against MCF-7 breast cancer cells, with clear selectivity patterns based on TfR levels. These results suggest that this novel isatin-based cytotoxin conjugated to a tumor targeting protein via an acid-labile linker warrants further preclinical testing.
Publisher: Public Library of Science (PLoS)
Date: 04-04-2009
Publisher: Elsevier BV
Date: 11-2000
Publisher: Elsevier BV
Date: 07-2014
Publisher: Bentham Science Publishers Ltd.
Date: 11-06-2019
DOI: 10.2174/1389450120666181204164140
Abstract: Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized in its early stages by synovial hyperplasia and inflammatory cell infiltration and later by irreversible joint tissue destruction. The plasminogen activation system (PAS) is associated with a wide range of physiological and pathophysiological states involving fibrinolysis, inflammation and tissue remodeling. Various components of the PAS are implicated in the pathophysiology of RA. Urokinase plasminogen activator (uPA) in particular is a pro-inflammatory mediator that appears to play an important role in the bone and cartilage destruction associated with RA. Clinical studies have shown that uPA and its receptor uPAR are overexpressed in synovia of patients with rheumatoid arthritis. Further, genetic knockdown and antibody-mediated neutralization of uPA have been shown to be protective against induction or progression of arthritis in animal models. The pro-arthritic role of uPA is differentiated from its haemodynamic counterpart, tissue plasminogen activator (tPA), which appears to play a protective role in RA animal models. This review summarises available evidence supporting the PAS as a critical determinant of RA pathogenesis and highlights opportunities for the development of novel uPAS-targeting therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 09-2023
Publisher: Elsevier BV
Date: 07-2011
Publisher: American Association for Cancer Research (AACR)
Date: 2007
DOI: 10.1158/1535-7163.MCT-06-0264
Abstract: Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by 213Bi-labeled plasminogen activator inhibitor type 2 (α-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of α-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human α-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg α-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d × 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d × 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of α-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. [Mol Cancer Ther 2007 (1):203–11]
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/NATURE21039
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JCONREL.2018.02.040
Abstract: The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption.
Publisher: Elsevier BV
Date: 05-1995
DOI: 10.1016/0925-4773(94)00344-M
Abstract: Limb development endures as an excellent model for pattern formation in vertebrates. We have identified Gnot1 as a member of a new homeobox gene subfamily. Gnot1 is expressed in a dynamic temporospatial distribution in the developing limb, initially correlating with regions destined to form distal structures and then becoming progressively more restricted to specific regions determined to give rise to wrist and ankle. Micro-surgical alteration of the developmental program of the limb reveals that Gnot1 is expressed in a position- and fate-dependent manner, responding both to signals from the apical ridge and the polarizing zone. Furthermore, Gnot1 activation by polarizing signals occurs temporally downstream of Hoxd gene activation, but well before the first appearance of condensations that will give rise to the carpus of the wrist. The features of Gnot1 expression suggest a role for this gene in regulating pattern formation during limb development.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-03-2019
Abstract: Pregnancy is a unique physiological state involving biological stresses that promote protein damage (misfolding) within the maternal body. Currently, little is known regarding how the maternal body copes with elevated protein misfolding in pregnancy. This is important, because the accumulation of misfolded proteins underlies many human disorders, including preecl sia, a serious complication of pregnancy. In this study, we show that pregnancy zone protein (PZP) efficiently inhibits the aggregation of misfolded proteins, including the amyloid beta peptide, which forms plaques in preecl sia and in Alzheimer’s disease. We propose that up-regulation of PZP is a major maternal adaptation that helps to maintain protein homeostasis during pregnancy. Moreover, pregnancy-independent up-regulation of PZP indicates that its chaperone function could be broadly important in humans.
Publisher: Frontiers Media SA
Date: 11-04-2022
Abstract: Cutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%–5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted cancer progression gene expression and pathway analysis in non-metastasizing (PRI-) and metastasizing primary (PRI+) cSCC tumors of the head and neck region, cognate lymph node metastases (MET), and matched sun-exposed skin (SES). The highest differentially expressed genes in metastatic (MET and PRI+) versus non-metastatic tumors (PRI-) and SES included PLAU , PLAUR , MMP1 , MMP10 , MMP13 , ITGA5 , VEGFA , and various inflammatory cytokine genes. Pathway enrichment analyses implicated these genes in cellular pathways and functions promoting matrix remodeling, cell survival and migration, and epithelial to mesenchymal transition, which were all significantly activated in metastatic compared to non-metastatic tumors (PRI-) and SES. We validated the overexpression of urokinase plasminogen activator receptor (uPAR, encoded by PLAUR ) in an extended patient cohort by demonstrating higher uPAR staining intensity in metastasizing tumors. As pathway analyses identified epidermal growth factor (EGF) as a potential upstream regulator of PLAUR , the effect of EGF on uPAR expression levels and cell motility was functionally validated in human metastatic cSCC cells. In conclusion, we propose that uPAR is an important driver of metastasis in cSCC and represents a potential therapeutic target in this disease.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.TIM.2005.05.006
Abstract: Streptococcus pyogenes (group A streptococcus) causes human skin and throat infections as well as highly invasive diseases including necrotizing fasciitis. Group A streptococcal infections and invasive disease have made a resurgence in developed countries during the past two decades. S. pyogenes use multiple pathways for the acquisition and activation of human plasminogen, securing potent proteolytic activity on the bacterial cell surface. Recent experimental evidence using a humanized transgenic mouse model suggests a crucial role for human plasminogen in the dissemination of S. pyogenes in vivo.
Publisher: Wiley
Date: 03-04-2017
DOI: 10.1002/HED.24765
Abstract: Cutaneous squamous cell carcinoma (SCC) is second only in incidence to basal cell carcinoma (BCC), effecting up to 500 000 people in the United States annually. Metastasis to regional lymph nodes occurs in approximately 5% of cases and imparts significant morbidity. Standard treatment in this group involves a combination of surgery and adjuvant radiation. Currently, there are no clinically useful biomarkers of metastatic potential in primary cutaneous SCC and histological predictors can be unreliable. The high level of mutational burden in normal UV-exposed skin has h ered the search for novel drivers of invasive disease, and indeed metastatic potential. This review outlines the clinical problems in high-risk and metastatic cutaneous SCCs, reviews the known genetic events and molecular mechanisms in high-risk primary cutaneous SCC and metastasis, and identifies avenues for further investigation and potential therapy.
Publisher: Wiley
Date: 08-2011
DOI: 10.1002/IJC.26156
Abstract: Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This mini-review summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs.
Publisher: Elsevier BV
Date: 12-1988
DOI: 10.1111/1523-1747.EP12477126
Abstract: Clinical evidence exists which suggests that normal pigment cell (melanocyte) function is subject to hormonal influences, but the nature of these interactions at a cellular level is poorly understood. We have investigated the effects of the vitamin D-derived secosteroid hormone 1 alpha-25, dihydroxyvitamin D3 (1,25(OH)2D3), the pituitary-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH), and the sex steroid beta-estradiol on melanocytes cultured from normal human foreskin. Human melanocytes specifically internalized 1,25(OH)2D3 with high affinity (Kd 0.5-0.8 nM). Incubation with 1,25(OH)2D3 (10(-9) M) for 48 h resulted in a 100% increase in 25-hydroxyvitamin D3-24-hydroxylase activity and a 50% increase in tyrosinase activity. There was no significant effect of 1,25(OH)2D3 on intracellular cyclic adenosine monophosphate (cAMP). In contrast to 1,25(OH)2D3, alpha-MSH at a concentration of 5 X 10(-7) M caused a sevenfold increase in intracellular cAMP after 12 min but only a modest increase (less than 20%) in melanocyte tyrosinase activity after 48 h. Incubation with beta-estradiol for 24 h caused a dose-dependent increase in tyrosinase activity. The maximal response varied from 145%-213% of basal activity depending on the donor source. These results indicate that melanocytes from normal human foreskin in culture have the capacity to respond directly to several hormones. They also suggest that these cells form a useful model to study the effect of various hormones on pigment cell function.
Publisher: Cold Spring Harbor Laboratory
Date: 25-09-2020
DOI: 10.1101/2020.09.24.20200048
Abstract: The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs 1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. 2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. 3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org ) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing % of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 × 10 −12 ), within the gene encoding dipeptidyl peptidase 9 ( DPP9 ), at chr12q24.13 (rs10735079, p =1.65 × 10 −8 ) in a gene cluster encoding antiviral restriction enzyme activators ( OAS1, OAS2, OAS3 ), and at chr21q22.1 (rs2236757, p = 4.99 × 10 −8 ) in the interferon receptor gene IFNAR2 . Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 × 10 −30 ). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2 , and high expression of TYK2 , to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Wiley
Date: 29-05-2008
DOI: 10.1096/FJ.08-109348
Abstract: A common mammalian defense mechanism employed to prevent systemic dissemination of invasive bacteria involves occlusion of local microvasculature and encapsulation of bacteria within fibrin networks. Acquisition of plasmin activity at the bacterial cell surface circumvents this defense mechanism, allowing invasive disease initiation. To facilitate this process, S. pyogenes secretes streptokinase, a plasminogen-activating protein. Streptokinase polymorphism exhibited by S. pyogenes isolates is well characterized. However, the functional differences displayed by these variants and the biological significance of this variation has not been elucidated. Phylogenetic analysis of ska sequences from 28 S. pyogenes isolates revealed 2 main sequence clusters (clusters 1 and 2). All strains secreted streptokinase, as determined by Western blotting, and were capable of acquiring cell surface plasmin activity after incubation in human plasma. Whereas culture supernatants from strains containing cluster 1 ska alleles also displayed soluble plasminogen activation activity, supernatants from strains containing cluster 2 ska alleles did not. Furthermore, plasminogen activation activity in culture supernatants from strains containing cluster 2 ska alleles could only be detected when plasminogen was prebound with fibrinogen. This study indicates that variant streptokinase proteins secreted by S. pyogenes isolates display differing plasminogen activation characteristics and may therefore play distinct roles in disease pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2011
DOI: 10.1038/NG.921
Publisher: Elsevier BV
Date: 02-2006
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Springer Science and Business Media LLC
Date: 04-2002
Publisher: Public Library of Science (PLoS)
Date: 17-06-2015
Publisher: Springer Science and Business Media LLC
Date: 06-04-2008
DOI: 10.1038/NG.121
Publisher: Springer Science and Business Media LLC
Date: 08-2010
DOI: 10.1038/NATURE09270
Publisher: MDPI AG
Date: 04-11-2020
DOI: 10.3390/ANTIBIOTICS9110775
Abstract: Group A Streptococcus (GAS) causes 700 million infections and accounts for half a million deaths per year. Antibiotic treatment failure rates of 20–40% have been observed. The role host cell glycans play in GAS biofilm formation in the context of GAS pharyngitis and subsequent antibiotic treatment failure has not been previously investigated. GAS serotype M12 GAS biofilms were assessed for biofilm formation on Detroit 562 pharyngeal cell monolayers following enzymatic removal of all N-linked glycans from pharyngeal cells with PNGase F. Removal of N-linked glycans resulted in an increase in biofilm biomass compared to untreated controls. Further investigation into the removal of terminal mannose and sialic acid residues with α1-6 mannosidase and the broad specificity sialidase (Sialidase A) also found that biofilm biomass increased significantly when compared to untreated controls. Increases in biofilm biomass were associated with increased production of extracellular polymeric substances (EPS). Furthermore, it was found that M12 GAS biofilms grown on untreated pharyngeal monolayers exhibited a 2500-fold increase in penicillin tolerance compared to planktonic GAS. Pre-treatment of monolayers with exoglycosidases resulted in a further doubling of penicillin tolerance in resultant biofilms. Lastly, an additional eight GAS emm-types were assessed for biofilm formation in response to terminal mannose and sialic acid residue removal. As seen for M12, biofilm biomass on monolayers increased following removal of terminal mannose and sialic acid residues. Collectively, these data demonstrate that pharyngeal cell surface glycan structures directly impact GAS biofilm formation in a strain and glycan specific fashion.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2018
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11582
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3667
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/ONC.2017.63
Publisher: MDPI AG
Date: 17-10-2023
Publisher: Bentham Science Publishers Ltd.
Date: 11-2011
Publisher: Frontiers Media SA
Date: 14-12-2022
DOI: 10.3389/FIMMU.2022.1060957
Abstract: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU ) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition. This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis. Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU .
Publisher: Springer Science and Business Media LLC
Date: 28-10-2014
DOI: 10.1038/NCOMMS6068
Abstract: Statins effectively lower LDL cholesterol levels in large studies and the observed interin idual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1 , not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Publisher: The Endocrine Society
Date: 02-2002
DOI: 10.1210/JC.87.2.752
Publisher: Elsevier BV
Date: 05-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2RA22859A
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41598-017-14403-Y
Abstract: Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human s les. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Elsevier BV
Date: 11-2012
Publisher: Public Library of Science (PLoS)
Date: 04-04-2013
Publisher: Elsevier BV
Date: 03-2014
Publisher: Elsevier BV
Date: 07-2004
Publisher: Springer Science and Business Media LLC
Date: 13-06-2015
Publisher: Springer Science and Business Media LLC
Date: 12-06-2008
DOI: 10.1038/NRC2400
Abstract: Tumour expression of the urokinase plasminogen activator correlates with invasive capacity. Consequently, inhibition of this serine protease by physiological inhibitors should decrease invasion and metastasis. However, of the two main urokinase inhibitors, high tumour levels of the type 1 inhibitor actually promote tumour progression, whereas high levels of the type 2 inhibitor decrease tumour growth and metastasis. We propose that the basis of this apparently paradoxical action of two similar serine protease inhibitors lies in key structural differences controlling interactions with components of the extracellular matrix and endocytosis-signalling co-receptors.
Publisher: Elsevier BV
Date: 10-2006
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S1040-8428(01)00113-5
Abstract: Targeted alpha therapy (TAT) can inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 were chelated to cancer specific monoclonal antibodies to form alpha-immunoconjugates (AIC) against melanoma, leukaemia, prostate and colorectal cancer, and to the plasminogen activator inhibitor type-2 (PAI2) to form alpha-PAI2 (API) against breast and prostate cancer. These conjugates were found to be highly stable, specific and cytotoxic in vitro. Melanoma and breast cancer tumour growth was observed in nude mouse models for untreated controls and non-specific AIC/API at 2 days post-subcutaneous inoculation of cancer cells. Complete inhibition of melanoma and breast cancer growth was found for local injections of AIC and API, respectively. Intra-lesional TAT of established melanoma showed that all melanomas regressed with 100 microCi injections of AIC. These results point to the potential application of local and systemic TAT in the management of metastatic cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/STROKEAHA.113.002186
Abstract: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 in iduals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 ( P =1.4×10 −8 ). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02 95% CI, 0.97–1.07 P =0.52) or its subtypes: cardioembolic (odds ratio, 1.07 95% CI, 0.97–1.16 P =0.17), large vessel disease (odds ratio, 0.98 95% CI, 0.89–1.07 P =0.60), and small vessel disease (odds ratio, 1.07 95% CI, 0.97–1.17 P =0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants ( P =0.18). We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532844
Abstract: AbstractPurpose: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. Experimental Design: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Results: Nonprogressing primary HNcSCC were characterized by higher CD8 sup + /sup and CD4 sup + /sup T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Conclusions: Effective responses from both CD8 sup + /sup and CD4 sup + /sup T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC. /
Publisher: American Chemical Society (ACS)
Date: 21-08-2018
Publisher: Springer Science and Business Media LLC
Date: 28-10-2012
DOI: 10.1038/NG.2435
Publisher: Springer Science and Business Media LLC
Date: 30-01-2017
DOI: 10.1038/NG.3768
Publisher: Elsevier BV
Date: 06-2003
Publisher: Elsevier BV
Date: 12-2010
Publisher: American Society for Microbiology
Date: 15-02-2007
DOI: 10.1128/JB.01218-06
Abstract: The migration of the human pathogen Streptococcus pyogenes (group A streptococcus) from localized to deep tissue sites may result in severe invasive disease, and sequestration of the host zymogen plasminogen appears crucial for virulence. Here, we describe a novel plasminogen-binding M protein, the p lasminogen-binding group A streptococcal M protein (PAM)- r elated p rotein (Prp). Prp is phylogenetically distinct from previously described plasminogen-binding M proteins of group A, C, and G streptococci. While competition experiments indicate that Prp binds plasminogen with a lower affinity than PAM (50% effective concentration = 0.34 μM), Prp nonetheless binds plasminogen with high affinity and at physiologically relevant concentrations of plasminogen ( K d = 7.8 nM). Site-directed mutagenesis of the putative plasminogen binding site indicates that unlike the majority of plasminogen receptors, Prp does not interact with plasminogen exclusively via lysine residues. Mutagenesis to alanine of lysine residues Lys 96 and Lys 101 reduced but did not abrogate plasminogen binding by Prp. Plasminogen binding was abolished only with the additional mutagenesis of Arg 107 and His 108 to alanine. Furthermore, mutagenesis of Arg 107 and His 108 abolished plasminogen binding by Prp despite the presence of Lys 96 and Lys 101 in the binding site. Thus, binding to plasminogen via arginine and histidine residues appears to be a conserved mechanism among plasminogen-binding M proteins.
Publisher: Springer Science and Business Media LLC
Date: 10-2015
DOI: 10.1007/S00535-015-1125-5
Abstract: Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 28-04-2011
DOI: 10.1016/J.CANLET.2011.01.018
Abstract: Up-regulation of the urokinase plasminogen activation (uPA) system leads to increased cancer invasion and metastasis. Plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and type-2 (PAI-2/SERPINB2) have similar uPA inhibitory properties yet PAI-1 promotes cell invasion by modulating cell adhesion and migration. High tumour PAI-2 levels are associated with improved prognoses. Herein we show that PAI-2 is capable of inhibiting uPA in the presence of PAI-1, particularly on adherent cells in the presence of vitronectin. This suggests that elevated levels of PAI-2 in the tumour microenvironment could outcompete PAI-1 for uPA inhibition through its inhibitory serpin function. However, PAI-1 modulated cell adhesion in a largely uPA-independent manner consequently PAI-2 could not counteract the effects of PAI-1 on adhesion/migration. Thus studies aimed at further characterising the interplay between PAI-1 and PAI-2 on uPA-dependent pro-invasive processes are warranted.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Baishideng Publishing Group Inc.
Date: 21-02-2018
Publisher: Elsevier BV
Date: 11-2001
Publisher: Springer Science and Business Media LLC
Date: 11-04-2010
DOI: 10.1038/NG.566
Publisher: Public Library of Science (PLoS)
Date: 05-06-2009
Publisher: Springer Science and Business Media LLC
Date: 06-06-2022
DOI: 10.1007/S12672-022-00510-4
Abstract: Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease. Epithelial-mesenchymal transition (EMT) is a driver of metastasis in many carcinomas, and cSCC is no exception. We aimed to provide a systematic overview of the clinical and experimental evidence for EMT in cSCC, with critical appraisal of type and quality of the methodology used. We then used this information as rationale for potential drug targets against advanced and metastatic cSCC. All primary literature encompassing clinical and cell-based or xenograft experimental studies reporting on the role of EMT markers or related signalling pathways in the progression of cSCC were considered. A screen of 3443 search results yielded 86 eligible studies comprising 44 experimental studies, 22 clinical studies, and 20 studies integrating both. From the clinical studies a timeline illustrating the alteration of EMT markers and related signalling was evident based on clinical progression of the disease. The experimental studies reveal connections of EMT with a multitude of factors such as genetic disorders, cancer-associated fibroblasts, and matrix remodelling via matrix metalloproteinases and urokinase plasminogen activator. Additionally, EMT was found to be closely tied to environmental factors as well as to stemness in cSCC via NFκB and β-catenin. We conclude that the canonical EGFR, canonical TGF-βR, PI3K/AKT and NFκB signalling are the four signalling pillars that induce EMT in cSCC and could be valuable therapeutic targets. Despite the complexity, EMT markers and pathways are desirable biomarkers and drug targets for the treatment of advanced or metastatic cSCC. Graphical Abstract
Publisher: Elsevier BV
Date: 09-2017
Publisher: Public Library of Science (PLoS)
Date: 26-06-2009
Publisher: MDPI AG
Date: 07-07-2020
DOI: 10.3390/PHARMACEUTICS12070641
Abstract: The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic N-alkylisatin (N-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in vitro and in vivo. Receptor-dependent uptake of PAI-2-functionalized liposomes was significantly higher in the uPA/uPAR overexpressing MDA-MB-231 breast cancer cell line relative to the low uPAR/uPAR expressing MCF-7 breast cancer cell line. Furthermore, N-AI cytotoxicity was enhanced in a receptor-dependent manner. In vivo, PAI-2 N-AI liposomes had a plasma half-life of 5.82 h and showed an increased accumulation at the primary tumor site in an orthotopic MDA-MB-231 BALB/c-Fox1nu/Ausb xenograft mouse model, relative to the non-functionalized liposomes, up to 6 h post-injection. These findings support the further development of N-AI-loaded PAI-2-functionalized liposomes for uPA/uPAR-positive breast cancer, especially against triple-negative breast cancer, for which the prognosis is poor and treatment is limited.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB00724H
Abstract: The relatively non-toxic family of cucurbit[n]uril, Q[n], have shown considerable potential in vitro as drug delivery agents, with only a few ex les of pharmacokinetic (PK) studies for drug⊂Q[n]. Drug-free Q[n] PK studies are the next step in determining the pharmacological applicability in their drug delivery potential. The results for the first PK and bio-distribution of drug-free
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2022
DOI: 10.1158/1078-0432.CCR-22-1332
Abstract: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 29-04-2009
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488947.V1
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: S. Karger AG
Date: 20-08-2014
DOI: 10.1159/000353754
Abstract: The globally significant human pathogen group A i Streptococcus /i (GAS) sequesters the host protease plasmin to the cell surface during invasive disease initiation. Recent evidence has shown that localized plasmin activity prevents opsonization of several bacterial species by key components of the innate immune system in vitro. Here we demonstrate that plasmin at the GAS cell surface resulted in degradation of complement factor C3b, and that plasminogen acquisition is associated with a decrease in C3b opsonization and neutrophil-mediated killing in vitro. Furthermore, the ability to acquire cell surface plasmin(ogen) correlates directly with a decrease in C3b opsonization, neutrophil phagocytosis, and increased bacterial survival in a humanized plasminogen mouse model of infection. These findings demonstrate that localized plasmin(ogen) plays an important role in facilitating GAS escape from the host innate immune response and increases bacterial virulence in the early stages of infection.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2014
DOI: 10.1038/NG.2897
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Bentham Science Publishers Ltd.
Date: 2012
DOI: 10.2174/156800912798888983
Abstract: Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic N-alkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20(th) and 1/10(th) of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2020
End Date: 2024
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2023
End Date: 2023
Funder: Tour de Cure
View Funded ActivityStart Date: 2021
End Date: 2026
Funder: Cancer Institute NSW
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2002
End Date: 2002
Funder: Australian Research Council
View Funded ActivityStart Date: 2011
End Date: 2011
Funder: Australian Research Council
View Funded ActivityStart Date: 2007
End Date: 2007
Funder: Australian Research Council
View Funded ActivityStart Date: 2009
End Date: 2009
Funder: Australian Research Council
View Funded ActivityStart Date: 2009
End Date: 12-2009
Amount: $225,600.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2001
End Date: 12-2002
Amount: $269,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2007
End Date: 12-2008
Amount: $200,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2011
End Date: 04-2012
Amount: $450,000.00
Funder: Australian Research Council
View Funded Activity