41 results found
Muhammed A, D'Alessio A, Enica A, et al., 2022, Predictive biomarkers of response to immune checkpoint inhibitors in hepatocellular carcinoma, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 22, Pages: 253-264, ISSN: 1473-7159
Page K, Martinson LJ, Fernandez-Garcia D, et al., 2021, Circulating tumor DNA profiling from breast cancer screening through to metastatic disease, JCO Precision Oncology, Vol: 5, Pages: 1768-1776, ISSN: 2473-4284
PURPOSE: We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS: Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS: One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION: We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.
Garcia DF, Nteliopoulos G, Hastings R, et al., 2021, Genomic copy number profiling of single CTCs reveals clonal evolution in metastatic breast cancer and identifies actionable targets for informing treatment decisions., Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Nteliopoulos G, Page K, Hills A, et al., 2021, Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients, Breast Cancer Research and Treatment, Vol: 188, Pages: 465-176, ISSN: 0167-6806
PurposeThere is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (< 0.5%) variant allele fraction (VAF).MethodsNinety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance.ResultsWe detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affecting ESR1, PIK3CA and TP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF < 1%. In longitudinal samples from progressing patients with endocrine resistance, we detected consistent alterations in sequential samples, most commonly in ESR1 and PIK3CA.ConclusionThis study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.
Bencomo-Alvarez AE, Rubio AJ, Olivas IM, et al., 2021, Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B, ONCOGENE, Vol: 40, Pages: 2697-2710, ISSN: 0950-9232
Rushton AJ, Nteliopoulos G, Shaw JA, et al., 2021, A Review of Circulating Tumour Cell Enrichment Technologies, CANCERS, Vol: 13
Rubio AJ, Olivas IM, Bencomo AE, et al., 2020, NF-kB associates with tyrosine kinase inhibitor resistance in chronic myeloid leukemia, AACR Annual Meeting, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Silvestri G, Trotta R, Stramucci L, et al., 2020, Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions, BLOOD CANCER DISCOVERY, Vol: 1, Pages: 48-67, ISSN: 2643-3230
Nteliopoulos G, Bazeos A, Claudiani S, et al., 2019, Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors, Haematologica, Vol: 104, Pages: 2400-2409, ISSN: 0390-6078
There are no validated molecular biomarkers to identify newly-diagnosed individuals with chronic-phase chronic myeloid leukaemia likely to respond poorly to imatinib and who might benefit from first-line treatment with a more potent second-generation tyrosine kinase-inhibitor. Our inability to predict these 'high-risk' individuals reflects the poorly understood heterogeneity of the disease. To investigate the potential of genetic variants in epigenetic modifiers as biomarkers at diagnosis, we used Ion Torrent next-generation sequencing of 71 candidate genes for predicting response to tyrosine kinase-inhibitors and probability of disease progression. 124 subjects with newly-diagnosed chronic-phase chronic myeloid leukaemia began with imatinib (n=62) or second-generation tyrosine kinase-inhibitors (n=62) and were classified as responders or non-responders based on the BCRABL1 transcript levels within the first year and the European LeukemiaNet criteria for failure. Somatic variants affecting 21 genes (e.g. ASXL1, IKZF1, DNMT3A, CREBBP) were detected in 30% of subjects, most of whom were non-responders (41% non-responders, 18% responders to imatinib, 38% non-responders, 25% responders to second-generation tyrosine kinase-inhibitors). The presence of variants predicted the rate of achieving a major molecular response, event-free survival, progression-free survival and chronic-myeloid-leukaemia-related survival in the imatinib but not the second-generation tyrosine kinase-inhibitors cohort. Rare germline variants had no prognostic significance irrespective of treatment while some pre-leukaemia variants suggest a multi-step development of chronic myeloid leukaemia. Our data suggest that identification of somatic variants at diagnosis facilitates stratification into imatinib responders/non-responders, thereby allowing earlier use of second-generation tyrosine kinase-inhibitors, which, in turn, may overcome the negative impact of such variants on disease progression.
Olivas IM, Lara J, Ellwood R, et al., 2019, NF-kappa B-Dependent Activation of the Proteasome Components, PSMD1 and PSMD3, As a Mechanism of Resistance to Imatinib, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Silvestri G, Trotta R, Stramucci L, et al., 2019, A 14q32.31 Genomic-Imprinted DLK1-DIO3 microrna promotes Leukemogenesis By Inducing Stem Cell Quiescence and Inhibiting NK Cell Anti-Cancer Immunity, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Claudiani S, Gatenby A, Szydlo R, et al., 2019, MR4 sustained for 12 months is associated with stable deep molecular responses in chronic myeloid leukemia, Haematologica, Vol: 104, Pages: 2206-2214, ISSN: 0390-6078
The majority of patients with newly diagnosed chronic myeloid leukaemia will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a real-life retrospective single-centre cohort study of 450 patients with chronic myeloid leukaemia in at least major molecular remission (MR3) to analyse the risk of loss of MR3 (defined as at least 2 consecutive RT-qPCR results >0.1% IS). Patient who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR <0.01% IS for 12 months) had a probability of loss of MR3 at 1 and 5 years of 0 and 2.6% (95% CI,1.2-5.4) respectively, compared to 4.4% (95% CI, 1.9-9.8) and 25.4% (95% CI, 16.7-36.7) respectively, in those who achieved sustained MR3 (sMR3) but not sMR4 (p <0.001). No patient who improved their response to a deep molecular level (at least MR4) lost MR3 if they were considered compliant, had no history of resistance and remained on standard dose TKI. MR4 maintained for at least 1 year represents a secure response threshold for patients with chronic myeloid leukaemia, after which no MR3 loss occurs if certain conditions are satisfied (standard TKI dose, full compliance and lack of previous TKI resistance). This finding may justify reduction of the frequency of hospital interaction, with an associated positive impact on quality of life, survivorship and economic burden to both patients and healthcare providers.
Branford S, Kim DDH, Apperley JF, et al., 2019, Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia., Leukemia, Vol: 33, Pages: 1835-1850, ISSN: 0887-6924
Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and g
Eiring AM, Ellwood R, Fiol CR, et al., 2019, Mechanisms of tyrosine kinase inhibitor resistance in chronic myeloid leukemia, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Alikian M, Ellwood R, Tatarinova O, et al., 2018, DNA-Based Digital PCR for the Quantification of Residual Disease in CML - Sensitivity or Specificity?, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Silvestri G, Stramucci L, Ellis J, et al., 2018, The tumor suppressor activity of miR-300 is detrimental for leukemia development but required for leukemia stem cell maintenance, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Claudiani S, Abulafia AS, Sabli I, et al., 2017, 10-Year Outcome of Chronic Myeloid Leukemia Patients Resistant to Frontline Imatinib, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Silvestri G, Stramucci L, Ellis J, et al., 2017, The Bone Marrow Niche Uses Mir-300 As a Biological Rheostat to Selectively Control Stem Cell-Driven Malignant Hematopoiesis and Innate Anti-Cancer Immunity, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Claudiani S, Gatenby A, Szydlo R, et al., 2017, Identification of a 'Safe Haven' for RT-qPCR Responses in CML: Can We Reduce the Frequency of Molecular Monitoring?, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Wahl S, Drong A, Lehne B, et al., 2016, Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity, Nature, Vol: 541, Pages: 81-+, ISSN: 0028-0836
Approximately 1.5 billion people worldwide are overweight oraffected by obesity, and are at risk of developing type 2 diabetes,cardiovascular disease and related metabolic and inflammatorydisturbances1,2. Although the mechanisms linking adiposity toassociated clinical conditions are poorly understood, recent studiessuggest that adiposity may influence DNA methylation3–6, a keyregulator of gene expression and molecular phenotype7. Here weuse epigenome-wide association to show that body mass index(BMI; a key measure of adiposity) is associated with widespreadchanges in DNA methylation (187 genetic loci with P<1×10−7,range P=9.2×10−8 to 6.0×10−46; n=10,261 samples). Geneticassociation analyses demonstrate that the alterations in DNAmethylation are predominantly the consequence of adiposity,rather than the cause. We find that methylation loci are enrichedfor functional genomic features in multiple tissues (P<0.05), andshow that sentinel methylation markers identify gene expressionsignatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to6.1×10−35, n=1,785 samples). The methylation loci identify genesinvolved in lipid and lipoprotein metabolism, substrate transportand inflammatory pathways. Finally, we show that the disturbancesin DNA methylation predict future development of type 2 diabetes(relative risk per 1 standard deviation increase in methylation riskscore: 2.3 (2.07–2.56); P=1.1×10−54). Our results provide newinsights into the biologic pathways influenced by adiposity, and mayenable development of new strategies for prediction and preventionof type 2 diabetes and other adverse clinical consequences of obesity
Reebye V, Saetrom P, Mintz PJ, et al., 2016, A short-activating RNA oligonucleotide targeting the islet beta-cell transcriptional factor MafA in CD34(+) cells, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 2, ISSN: 2162-2531
Upon functional loss of insulin producing islet β-cells, some patients with diabetes become dependent on life-long insulin supplementation therapy. Bioengineering surrogate insulin producing cells is an alternative replacement strategy. We have developed a novel approach using short-activating RNA oligonucleotides to differentiate adult human CD34+ cells into insulin-secreting cells. By transfecting RNA to increase transcript levels of the master regulator of insulin biosynthesis, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), several pancreatic endodermal genes were upregulated during the differentiation procedure. These included Pancreatic and duodenal homeobox gene-1 (PDX1), Neurogenin 3, NeuroD, and NK6 homeobox 1 (NKx6-1). Differentiated CD34+ cells also expressed glucokinase, glucagon-like peptide 1 receptor (GLP1R), sulfonylurea receptor-1 (SUR1) and phogrin'all essential for glucose sensitivity and insulin secretion. The differentiated cells appropriately processed C-peptide and insulin in response to increasing glucose stimulation as shown by enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting analysis, western blotting, and immunofluorescence staining. We provide a new approach using short-activating RNA in developing insulin producing surrogate cells for treating diabetes.
Nteliopoulos G, Bazeos A, Gerrard G, et al., 2016, Somatic Mutations in Epigenetic Modifiers Identified Using Next Generation Sequencing (NGS) in Diagnostic Samples of CML-CP Can Predict Poor Outcome on Imatinib Which Is Abrogated By Frontline 2G-TKI Therapy, 58th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Nteliopoulos G, Bazeos A, Gerrard G, et al., 2016, PRESENCE OF SOMATIC AND GERMLINE MUTATIONS IN EPIGENETIC MODIFIERS IN CML-CP, 21st Congress of the European Hematology Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 235-235, ISSN: 0390-6078
Nteliopoulos G, Gerrard G, Foong HE, et al., 2015, MUTATION ANALYSIS OF EPIGENETIC MODIFIERS IN CHRONIC PHASE CML USING NEXT GENERATION SEQUENCING, 20th Congress of European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 169-170, ISSN: 0390-6078
Mintz PJ, Huang K-W, Reebye V, et al., 2014, Exploiting human CD34(+) stem cell-conditioned medium for tissue repair, Molecular Therapy, Vol: 22, Pages: 149-159, ISSN: 1525-0016
Despite the progress in our understanding of genes essential for stem cell regulation and development, little is known about the factors secreted by stem cells and their effect on tissue regeneration. In particular, the factors secreted by human CD34+ cells remain to be elucidated. We have approached this challenge by performing a cytokine/growth factor microarray analysis of secreted soluble factors in medium conditioned by adherent human CD34+ cells. Thirty-two abundantly secreted factors have been identified, all of which are associated with cell proliferation, survival, tissue repair, and wound healing. The cultured CD34+ cells expressed known stem cell genes such as Nanog, Oct4, Sox2, c-kit, and HoxB4. The conditioned medium containing the secreted factors prevented cell death in liver cells exposed to liver toxin in vitro via inhibition of the caspase-3 signaling pathway. More importantly, in vivo studies using animal models of liver damage demonstrated that injection of the conditioned medium could repair damaged liver tissue (significant reduction in the necroinflammatory activity), as well as enable the animals to survive. Thus, we demonstrate that medium conditioned by human CD34+ cells has the potential for therapeutic repair of damaged tissue in vivo.
Grinfeld J, Gerrard G, Alikian M, et al., 2013, A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 163, Pages: 631-639, ISSN: 0007-1048
Nikolakopoulou Z, Nteliopoulos G, Michael-Titus AT, et al., 2013, Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2., Carcinogenesis, Vol: 34, Pages: 2716-2725
The long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs)-eicosapentaenoic acid (EPA) and its metabolite docosahexaenoic acid (DHA)-inhibit cancer formation in vivo, but their mechanism of action is unclear. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibition have both been associated with the induction of tumour cell apoptosis by n-3 PUFAs. We show here that low doses of EPA, in particular, inhibited the growth of premalignant and malignant keratinocytes more than the growth of normal counterparts by a combination of cell cycle arrest and apoptosis. The growth inhibition of the oral squamous cell carcinoma (SCC) lines, but not normal keratinocytes, by both n-3 PUFAs was associated with epidermal growth factor receptor (EGFR) autophosphorylation, a sustained phosphorylation of ERK1/2 and its downstream target p90RSK but not with phosphorylation of the PI3 kinase target Akt. Inhibition of EGFR with either the EGFR kinase inhibitor AG1478 or an EGFR-blocking antibody inhibited ERK1/2 phosphorylation, and the blocking antibody partially antagonized growth inhibition by EPA but not by DHA. DHA generated more reactive oxygen species and activated more c-jun N-terminal kinase than EPA, potentially explaining its increased toxicity to normal keratinocytes. Our results show that, in part, EPA specifically inhibits SCC growth and development by creating a sustained signalling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supraoptimal level, supporting the chemopreventive potential of EPA, whose toxicity to normal cells might be reduced further by blocking its metabolism to DHA. Furthermore, ERK1/2 phosphorylation may have potential as a biomarker of n-3 PUFA function in vivo.
Bazeos A, Lowe R, Nteliopoulos G, et al., 2013, THE CML EPIGENOME SHOWS DYNAMIC CHANGES IN THE CD34+COMPARTMENT IN PATIENTS WHO ACHIEVE COMPLETE CYTOGENETIC RESPONSE ON TYROSINE KINASE INHIBITORS, Publisher: FERRATA STORTI FOUNDATION, Pages: 255-255, ISSN: 0390-6078
Hu M, Khorashad JS, Chaidos A, et al., 2012, Contrasting Effects of Enhanced Sirt1 Activity in Normal and BCR-ABL1-Depedent Haematopoiesis, 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Nteliopoulos G, Gordon MY, 2012, Protein Segregation Between Dividing Hematopoietic Progenitor Cells in the Determination of the Symmetry/Asymmetry of Cell Division, STEM CELLS AND DEVELOPMENT, Vol: 21, Pages: 2565-2580, ISSN: 1547-3287
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