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  1. Artikel ; Online: Upregulation of IFNɣ-mediated chemokines dominate the immune transcriptome of muscle-invasive urothelial carcinoma

    Ekaterina Olkhov-Mitsel / Anjelica Hodgson / Stan K. Liu / Danny Vesprini / Jane Bayani / John M. S. Bartlett / Bin Xu / Michelle R. Downes

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Band 10

    Abstract: Abstract Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed ... ...

    Abstract Abstract Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2022-01-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: EMT in Breast Carcinoma—A Review

    Joema Felipe Lima / Sharon Nofech-Mozes / Jane Bayani / John M. S. Bartlett

    Journal of Clinical Medicine, Vol 5, Iss 7, p

    2016  Band 65

    Abstract: The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) ...

    Abstract The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) are caused by invasion and metastasis. The EMT plays an important role in invasion and subsequent metastasis. Several distinct biological events integrate a cascade that leads not only to a change from an epithelial to mesenchymal phenotype, but allows for detachment, migration, invasion and ultimately, colonization of a second site. Understanding the biological intricacies of the EMT may provide important insights that lead to the development of therapeutic targets in pre-invasive and invasive breast cancer, and could be used as biomarkers identifying tumor subsets with greater chances of recurrence, metastasis and therapeutic resistance leading to death.
    Schlagwörter EMT ; breast ; cancer ; invasion ; metastasis ; Medicine ; R
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2016-07-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Computational approaches to support comparative analysis of multiparametric tests

    John M S Bartlett / Jane Bayani / Elizabeth N Kornaga / Patrick Danaher / Cheryl Crozier / Tammy Piper / Cindy Q Yao / Janet A Dunn / Paul C Boutros / Robert C Stein / OPTIMA Trial Management Group

    PLoS ONE, Vol 15, Iss 9, p e

    Modelling versus Training.

    2020  Band 0238593

    Abstract: Multiparametric assays for risk stratification are widely used in the management of breast cancer, with applications being developed for a number of other cancer settings. Recent data from multiple sources suggests that different tests may provide ... ...

    Abstract Multiparametric assays for risk stratification are widely used in the management of breast cancer, with applications being developed for a number of other cancer settings. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. There is an increasing need for robust methods to support cost effective comparisons of test performance in multiple settings. The derivation of similar risk classifications using genes comprising the following multi-parametric tests Oncotype DX® (Genomic Health.), Prosigna™ (NanoString Technologies, Inc.), MammaPrint® (Agendia Inc.) was performed using different computational approaches. Results were compared to the actual test results. Two widely used approaches were applied, firstly computational "modelling" of test results using published algorithms and secondly a "training" approach which used reference results from the commercially supplied tests. We demonstrate the potential for errors to arise when using a "modelling" approach without reference to real world test results. Simultaneously we show that a "training" approach can provide a highly cost-effective solution to the development of real-world comparisons between different multigene signatures. Comparisons between existing multiparametric tests is challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. We present an approach, modelled in breast cancer, which can provide health care providers and researchers with the potential to perform robust and meaningful comparisons between multigene tests in a cost-effective manner. We demonstrate that whilst viable estimates of gene signatures can be derived from modelling approaches, in our study using a training approach allowed a close approximation to true signature results.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 310
    Sprache Englisch
    Erscheinungsdatum 2020-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: ISOWN

    Irina Kalatskaya / Quang M. Trinh / Melanie Spears / John D. McPherson / John M. S. Bartlett / Lincoln Stein

    Genome Medicine, Vol 9, Iss 1, Pp 1-

    accurate somatic mutation identification in the absence of normal tissue controls

    2017  Band 18

    Abstract: Abstract Background A key step in cancer genome analysis is the identification of somatic mutations in the tumor. This is typically done by comparing the genome of the tumor to the reference genome sequence derived from a normal tissue taken from the ... ...

    Abstract Abstract Background A key step in cancer genome analysis is the identification of somatic mutations in the tumor. This is typically done by comparing the genome of the tumor to the reference genome sequence derived from a normal tissue taken from the same donor. However, there are a variety of common scenarios in which matched normal tissue is not available for comparison. Results In this work, we describe an algorithm to distinguish somatic single nucleotide variants (SNVs) in next-generation sequencing data from germline polymorphisms in the absence of normal samples using a machine learning approach. Our algorithm was evaluated using a family of supervised learning classifications across six different cancer types and ~1600 samples, including cell lines, fresh frozen tissues, and formalin-fixed paraffin-embedded tissues; we tested our algorithm with both deep targeted and whole-exome sequencing data. Our algorithm correctly classified between 95 and 98% of somatic mutations with F1-measure ranges from 75.9 to 98.6% depending on the tumor type. We have released the algorithm as a software package called ISOWN (Identification of SOmatic mutations Without matching Normal tissues). Conclusions In this work, we describe the development, implementation, and validation of ISOWN, an accurate algorithm for predicting somatic mutations in cancer tissues in the absence of matching normal tissues. ISOWN is available as Open Source under Apache License 2.0 from https://github.com/ikalatskaya/ISOWN .
    Schlagwörter Next-generation sequencing ; Somatic mutation ; Matching normal tissue ; Variant classification ; Medicine ; R ; Genetics ; QH426-470
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2017-06-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Correction

    Sherene Loi / Stefan Michiels / Jose Baselga / John M S Bartlett / Sandeep K Singhal / Vicky S Sabine / Andrew H Sims / Tarek Sahmoud / J Michael Dixon / Martine J Piccart / Christos Sotiriou

    PLoS ONE, Vol 14, Iss 4, p e

    PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer.

    2019  Band 0216175

    Abstract: This corrects the article DOI:10.1371/journal.pone.0053292.]. ...

    Abstract [This corrects the article DOI:10.1371/journal.pone.0053292.].
    Schlagwörter Medicine ; R ; Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2019-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Reliability and performance of commercial RNA and DNA extraction kits for FFPE tissue cores.

    Palak G Patel / Shamini Selvarajah / Karl-Philippe Guérard / John M S Bartlett / Jacques Lapointe / David M Berman / John B A Okello / Paul C Park

    PLoS ONE, Vol 12, Iss 6, p e

    2017  Band 0179732

    Abstract: Cancer biomarker studies often require nucleic acid extraction from limited amounts of formalin-fixed, paraffin-embedded (FFPE) tissues, such as histologic sections or needle cores. A major challenge is low quantity and quality of extracted nucleic acids, ...

    Abstract Cancer biomarker studies often require nucleic acid extraction from limited amounts of formalin-fixed, paraffin-embedded (FFPE) tissues, such as histologic sections or needle cores. A major challenge is low quantity and quality of extracted nucleic acids, which can limit our ability to perform genetic analyses, and have a significant influence on overall study design. This study was aimed at identifying the most reliable and reproducible method of obtaining sufficient high-quality nucleic acids from FFPE tissues. We compared the yield and quality of nucleic acids from 0.6-mm FFPE prostate tissue cores across 16 DNA and RNA extraction protocols, using 14 commercially available kits. Nucleic acid yield was determined by fluorometry, and quality was determined by spectrophotometry. All protocols yielded nucleic acids in quantities that are compatible with downstream molecular applications. However, the protocols varied widely in the quality of the extracted RNA and DNA. Four RNA and five DNA extraction protocols, including protocols from two kits for dual-extraction of RNA and DNA from the same tissue source, were prioritized for further quality assessment based on the yield and purity of their products. Specifically, their compatibility with downstream reactions was assessed using both NanoString nCounter gene expression assays and reverse-transcriptase real-time PCR for RNA, and methylation-specific PCR assays for DNA. The kit deemed most suitable for FFPE tissue was the AllPrep kit by Qiagen because of its yield, quality, and ability to purify both RNA and DNA from the same sample, which would be advantageous in biomarker studies.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 612
    Sprache Englisch
    Erscheinungsdatum 2017-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer.

    Deena M A Gendoo / Robert E Denroche / Amy Zhang / Nikolina Radulovich / Gun Ho Jang / Mathieu Lemire / Sandra Fischer / Dianne Chadwick / Ilinca M Lungu / Emin Ibrahimov / Ping-Jiang Cao / Lincoln D Stein / Julie M Wilson / John M S Bartlett / Ming-Sound Tsao / Neesha Dhani / David Hedley / Steven Gallinger / Benjamin Haibe-Kains

    PLoS Computational Biology, Vol 15, Iss 1, p e

    2019  Band 1006596

    Abstract: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to ... ...

    Abstract Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2019-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer.

    Sherene Loi / Stefan Michiels / Jose Baselga / John M S Bartlett / Sandeep K Singhal / Vicky S Sabine / Andrew H Sims / Tarek Sahmoud / J Michael Dixon / Martine J Piccart / Christos Sotiriou

    PLoS ONE, Vol 8, Iss 1, p e

    2013  Band 53292

    Abstract: The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR ... ...

    Abstract The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2013-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel ; Online: An Increase in N-Ras Expression is Associated with Development of Hormone Refractory Prostate Cancer in a Subset of Patients

    Pamela Traynor / Liane M. McGlynn / Rono Mukhergee / Samuel J. S. Grimsley / John M. S. Bartlett / Joanne Edwards

    Disease Markers, Vol 24, Iss 3, Pp 157-

    2008  Band 165

    Abstract: Protein expression of H, K and N-Ras was assessed in hormone sensitive and hormone refractory prostate tumour pairs from 61 patients by immunohistochemistry. Expression of H-Ras and K- Ras was not associated with any known clinical parameters. In ... ...

    Abstract Protein expression of H, K and N-Ras was assessed in hormone sensitive and hormone refractory prostate tumour pairs from 61 patients by immunohistochemistry. Expression of H-Ras and K- Ras was not associated with any known clinical parameters. In contrast an increase in N-Ras membrane expression in the transition from hormone sensitive to hormone refractory prostate cancer was associated with shorter time to relapse (p = 0.01) and shorter disease specific survival (p = 0.008). In addition, patients with an increase in N-Ras membrane expression had lower levels of PSA at relapse (p = 0.02) and expression correlated with phosphorylated MAP kinase (p = 0.010) and proliferation index (Ki67, p = 0.02). These results suggest that in a subgroup patients N-Ras expression is associated with development of hormone refractory prostate cancer via activation of the MAP kinase cascade.
    Schlagwörter Medicine (General) ; R5-920
    Sprache Englisch
    Erscheinungsdatum 2008-01-01T00:00:00Z
    Verlag Hindawi Publishing Corporation
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  10. Artikel ; Online: Pathway-based subnetworks enable cross-disease biomarker discovery

    Syed Haider / Cindy Q. Yao / Vicky S. Sabine / Michal Grzadkowski / Vincent Stimper / Maud H. W. Starmans / Jianxin Wang / Francis Nguyen / Nathalie C. Moon / Xihui Lin / Camilla Drake / Cheryl A. Crozier / Cassandra L. Brookes / Cornelis J. H. van de Velde / Annette Hasenburg / Dirk G. Kieback / Christos J. Markopoulos / Luc Y. Dirix / Caroline Seynaeve /
    Daniel W. Rea / Arek Kasprzyk / Philippe Lambin / Pietro Lio’ / John M. S. Bartlett / Paul C. Boutros

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Band 12

    Abstract: Accurate and actionable biomarkers that integrate diverse molecular, functional and clinical information hold great promise in precision medicine. Here, the authors develop SIMMS, a method for pathway-based cross-disease biomarker discovery. ...

    Abstract Accurate and actionable biomarkers that integrate diverse molecular, functional and clinical information hold great promise in precision medicine. Here, the authors develop SIMMS, a method for pathway-based cross-disease biomarker discovery.
    Schlagwörter Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2018-11-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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