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Article ; Online: Harnessing the cytotoxic granule exocytosis to augment the efficacy of T-cell-engaging bispecific antibody therapy.

Casey, Mika / Lee, Carol / Hoyte, Sharon M / Johnston, Rebecca L / Kwok, Wing Yu / Law, Soi Cheng / Gandhi, Maher K / Harrison, Simon J / Nakamura, Kyohei

Haematologica

2024

Abstract: T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating ... ...

Abstract	T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be established, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This approach reveals IL-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characterization strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma-killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cytotoxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.
Language	English
Publishing date	2024-01-25
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284435
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Article ; Online: Generalising uncertainty improves accuracy and safety of deep learning analytics applied to oncology.

MacDonald, Samual / Foley, Helena / Yap, Melvyn / Johnston, Rebecca L / Steven, Kaiah / Koufariotis, Lambros T / Sharma, Sowmya / Wood, Scott / Addala, Venkateswar / Pearson, John V / Roosta, Fred / Waddell, Nicola / Kondrashova, Olga / Trzaskowski, Maciej

Scientific reports

2023 Volume 13, Issue 1, Page(s) 7395

Abstract: Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated ...

Abstract	Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models for predicting cancer of unknown primary, using three RNA-seq datasets with 10,968 samples across 57 cancer types. Our results highlight that simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation. Moreover, we designed a prototypical metric-the area between development and production curve (ADP), which evaluates the accuracy loss when deploying models from development to production. Using ADP, we demonstrate that Bayesian DL improves accuracy under data distributional shifts when utilising 'uncertainty thresholding'. In summary, Bayesian DL is a promising approach for generalising uncertainty, improving performance, transparency, and safety of DL models for deployment in the real world.
MeSH term(s)	Bayes Theorem ; Deep Learning ; Reproducibility of Results ; Uncertainty ; Medical Oncology
Language	English
Publishing date	2023-05-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-31126-5
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Article: Lentiviral Transduction-based CRISPR/Cas9 Editing of

Du, Xiaofeng / McManus, Donald P / French, Juliet D / Sivakumaran, Haran / Johnston, Rebecca L / Kondrashova, Olga / Fogarty, Conor E / Jones, Malcolm K / You, Hong

Current genomics

2023 Volume 24, Issue 3, Page(s) 155–170

Abstract: Background: Recent studies on CRISPR/Cas9-mediated gene editing in : Methods: To improve the efficiency of CRISPR/Cas9 genome editing in schistosomes, we used lentivirus, which has been effectively used for gene editing in mammalian cells, to deliver ...

Abstract	Background: Recent studies on CRISPR/Cas9-mediated gene editing in Methods: To improve the efficiency of CRISPR/Cas9 genome editing in schistosomes, we used lentivirus, which has been effectively used for gene editing in mammalian cells, to deliver plasmid DNA encoding Cas9 nuclease, a sgRNA targeting acetylcholinesterase ( Results: MCherry fluorescence was observed in transduced eggs, schistosomula, and adult worms, indicating that the CRISPR components had been delivered into these parasite stages by lentivirus. In addition, clearly changed phenotypes were observed in Conclusion: Taken together, electroporation is more efficient than lentiviral transduction in the delivery of CRISPR/Cas9 into schistosomes for programmed genome editing. The exploration of tactics for enhancing CRISPR/Cas9 gene editing provides the basis for the future improvement of programmed genome editing in
Language	English
Publishing date	2023-12-21
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2033677-9
ISSN	1875-5488 ; 1389-2029
ISSN (online)	1875-5488
ISSN	1389-2029
DOI	10.2174/1389202924666230823094608
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Article ; Online: Performance of tumour microenvironment deconvolution methods in breast cancer using single-cell simulated bulk mixtures.

Tran, Khoa A / Addala, Venkateswar / Johnston, Rebecca L / Lovell, David / Bradley, Andrew / Koufariotis, Lambros T / Wood, Scott / Wu, Sunny Z / Roden, Daniel / Al-Eryani, Ghamdan / Swarbrick, Alexander / Williams, Elizabeth D / Pearson, John V / Kondrashova, Olga / Waddell, Nicola

Nature communications

2023 Volume 14, Issue 1, Page(s) 5758

Abstract: Cells within the tumour microenvironment (TME) can impact tumour development and influence treatment response. Computational approaches have been developed to deconvolve the TME from bulk RNA-seq. Using scRNA-seq profiling from breast tumours we simulate ...

Abstract	Cells within the tumour microenvironment (TME) can impact tumour development and influence treatment response. Computational approaches have been developed to deconvolve the TME from bulk RNA-seq. Using scRNA-seq profiling from breast tumours we simulate thousands of bulk mixtures, representing tumour purities and cell lineages, to compare the performance of nine TME deconvolution methods (BayesPrism, Scaden, CIBERSORTx, MuSiC, DWLS, hspe, CPM, Bisque, and EPIC). Some methods are more robust in deconvolving mixtures with high tumour purity levels. Most methods tend to mis-predict normal epithelial for cancer epithelial as tumour purity increases, a finding that is validated in two independent datasets. The breast cancer molecular subtype influences this mis-prediction. BayesPrism and DWLS have the lowest combined numbers of false positives and false negatives, and have the best performance when deconvolving granular immune lineages. Our findings highlight the need for more single-cell characterisation of rarer cell types, and suggest that tumour cell compositions should be considered when deconvolving the TME.
MeSH term(s)	Animals ; Tumor Microenvironment ; Mammary Neoplasms, Animal ; Cell Lineage ; Music ; RNA-Seq
Language	English
Publishing date	2023-09-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41385-5
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Article ; Online: Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

McKinnon, Brett D / Lukowski, Samuel W / Mortlock, Sally / Crawford, Joanna / Atluri, Sharat / Subramaniam, Sugarniya / Johnston, Rebecca L / Nirgianakis, Konstantinos / Tanaka, Keisuke / Amoako, Akwasi / Mueller, Michael D / Montgomery, Grant W

Communications biology

2022 Volume 5, Issue 1, Page(s) 600

Abstract: Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated ... ...

Abstract	Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.
MeSH term(s)	Cell Differentiation ; Endometriosis/genetics ; Endometrium ; Female ; Fibroblasts/pathology ; Humans ; Mesenchymal Stem Cells
Language	English
Publishing date	2022-06-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03541-3
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Article ; Online: A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies.

Wasielewska, Joanna M / Chaves, Juliana C S / Johnston, Rebecca L / Milton, Laura A / Hernández, Damián / Chen, Liyu / Song, Jae / Lee, Wendy / Leinenga, Gerhard / Nisbet, Rebecca M / Pébay, Alice / Götz, Jürgen / White, Anthony R / Oikari, Lotta E

Theranostics

2022 Volume 12, Issue 16, Page(s) 6826–6847

Abstract: ... Rationale: ... The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles ( ... ...

Abstract	Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS<sup>+MB</sup>) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS<sup>+MB</sup> is safe, however, the effects of FUS<sup>+MB</sup> on human BBB cells, especially in the context of AD, remain sparsely investigated. In addition, there currently are no cell platforms to test for FUS<sup>+MB</sup>-mediated drug delivery. Methods: Here we generated BBB cells (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high sporadic AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We established mono- and co-culture models of human sporadic AD and control BBB cells to investigate the effects of FUS<sup>+MB</sup> on BBB cell phenotype and to screen for the delivery of two potentially therapeutic AD antibodies, an Aducanumab-analogue (Aduhelm<sup>TM</sup>; anti-amyloid-β) and a novel anti-Tau antibody, RNF5. We then developed a novel hydrogel-based 2.5D BBB model as a step towards a more physiologically relevant FUS<sup>+MB</sup> drug delivery platform. Results: When compared to untreated cells, the delivery of Aducanumab-analogue and RNF5 was significantly increased (up to 1.73 fold), across the Transwell-based BBB models following FUS<sup>+MB</sup> treatment. Our results also demonstrated the safety of FUS<sup>+MB</sup> indicated by minimal changes in iBEC transcriptome as well as little or no changes in iBEC or iAstrocyte viability and inflammatory responses within the first 24 h post FUS<sup>+MB</sup>. Furthermore, we demonstrated successful iBEC barrier formation in our novel 2.5D hydrogel-based BBB model with significantly increased delivery (1.4 fold) of Aducanumab-analogue following FUS<sup>+MB</sup>. Conclusion: Our results demonstrate a robust and reproducible approach to utilize patient cells for FUS<sup>+MB</sup>-mediated drug delivery screening in vitro. With such a cell platform for FUS<sup>+MB</sup> research previously not reported, it has the potential to identify novel FUS<sup>+MB</sup>-deliverable drugs as well as screen for cell- and patient-specific effects of FUS<sup>+MB</sup>, accelerating the use of FUS<sup>+MB</sup> as a therapeutic modality in AD.
MeSH term(s)	Humans ; Alzheimer Disease/drug therapy ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/metabolism ; Blood-Brain Barrier ; Brain/physiology ; Drug Delivery Systems/methods ; Hydrogels ; Microbubbles ; Antibodies, Monoclonal, Humanized/administration & dosage
Chemical Substances	aducanumab (105J35OE21) ; Apolipoprotein E3 ; Apolipoprotein E4 ; Hydrogels ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2022-09-25
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.72685
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Article ; Online: Verifying explainability of a deep learning tissue classifier trained on RNA-seq data.

Yap, Melvyn / Johnston, Rebecca L / Foley, Helena / MacDonald, Samual / Kondrashova, Olga / Tran, Khoa A / Nones, Katia / Koufariotis, Lambros T / Bean, Cameron / Pearson, John V / Trzaskowski, Maciej / Waddell, Nicola

Scientific reports

2021 Volume 11, Issue 1, Page(s) 2641

Abstract: For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within ... ...

Abstract	For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within high-dimensional data is unclear. To test the reliability of the explainability model SHapley Additive exPlanations (SHAP), we developed a convolutional neural network to predict tissue classification from Genotype-Tissue Expression (GTEx) RNA-seq data representing 16,651 samples from 47 tissues. Our classifier achieved an average F1 score of 96.1% on held-out GTEx samples. Using SHAP values, we identified the 2423 most discriminatory genes, of which 98.6% were also identified by differential expression analysis across all tissues. The SHAP genes reflected expected biological processes involved in tissue differentiation and function. Moreover, SHAP genes clustered tissue types with superior performance when compared to all genes, genes detected by differential expression analysis, or random genes. We demonstrate the utility and reliability of SHAP to explain a deep learning model and highlight the strengths of applying ML to transcriptome data.
MeSH term(s)	Algorithms ; Deep Learning ; Genotype ; Humans ; Machine Learning ; Neural Networks, Computer ; Organ Specificity/genetics ; RNA-Seq
Language	English
Publishing date	2021-01-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-81773-9
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Article ; Online: Donor bone marrow-derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice.

Adams, Rachael C / Carter-Cusack, Dylan / Shaikh, Samreen N / Llanes, Genesis T / Johnston, Rebecca L / Quaife-Ryan, Gregory / Boyle, Glen / Koufariotis, Lambros T / Möller, Andreas / Blazar, Bruce R / Vukovic, Jana / MacDonald, Kelli P A

Blood

2021 Volume 139, Issue 9, Page(s) 1389–1408

Abstract: Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction ...

Abstract	Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+ donor bone marrow (BM)-derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
MeSH term(s)	Animals ; Bone Marrow Transplantation ; Chronic Disease ; Female ; Graft vs Host Disease/immunology ; Histocompatibility Antigens Class II/immunology ; Macrophages/immunology ; Mice ; Neuroinflammatory Diseases/immunology
Chemical Substances	Histocompatibility Antigens Class II
Language	English
Publishing date	2021-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021011671
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Article ; Online: A gene expression-based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma.

Johnston, Rebecca L / Mottok, Anja / Chan, Fong Chun / Jiang, Aixiang / Diepstra, Arjan / Visser, Lydia / Telenius, Adèle / Gascoyne, Randy D / Friedman, Debra L / Schwartz, Cindy L / Kelly, Kara M / Scott, David W / Horton, Terzah M / Steidl, Christian

Blood

2021 Volume 139, Issue 6, Page(s) 889–893

Abstract: Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools ...

Abstract	Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
MeSH term(s)	Child ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Hodgkin Disease/diagnosis ; Hodgkin Disease/genetics ; Humans ; Models, Biological ; Prognosis ; Progression-Free Survival ; Tumor Microenvironment
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021011941
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Article ; Online: Routine Molecular Profiling in Both Resectable and Unresectable Pancreatic Adenocarcinoma: Relevance of Cytologic Samples.

Redegalli, Miriam / Grassini, Greta / Magliacane, Gilda / Pecciarini, Lorenza / Schiavo Lena, Marco / Smart, Chanel E / Johnston, Rebecca L / Waddell, Nicola / Maestro, Roberta / Macchini, Marina / Orsi, Giulia / Petrone, Maria Chiara / Rossi, Gemma / Balzano, Gianpaolo / Falconi, Massimo / Arcidiacono, Paolo G / Reni, Michele / Doglioni, Claudio / Cangi, Maria Giulia

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

2022 Volume 21, Issue 11, Page(s) 2825–2833

Abstract: Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease, for which it is crucial to promptly detect actionable and prognostic alterations to drive specific therapeutic decisions, regardless of tumor resectability status. ...

Abstract	Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease, for which it is crucial to promptly detect actionable and prognostic alterations to drive specific therapeutic decisions, regardless of tumor resectability status. Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) is of key importance for PDAC diagnosis and can contribute significantly to tumor molecular profiling. Methods: Comprehensive genomic profile by targeted next-generation sequencing (NGS) was performed on 2 independent PDAC patient cohorts. Cohort 1 consisted of 77 patients with resectable PDAC for whom the histologic sample at the time of resection was available; for 56 patients cytologic specimens at the time of diagnosis also were obtained by EUS-FNA. Cohort 2 consisted of 20 patients with unresectable PDAC, for whom only the EUS-FNA cytologic sample was available. Results: In cohort 1, a complete concordant mutational profile between the cytologic sample at diagnosis and the corresponding histologic specimen after surgery was observed in 88% of the cases, proving the ability to detect potential clinically relevant alterations in cytologic samples by NGS analysis. Notably, clinically actionable mutations were identified in 20% of patients. In cohort 2, comprehensive mutational profiling was obtained successfully for all samples. Consistent with the findings of cohort 1, KRAS, TP53, CDKN2A, and SMAD4 were the most altered genes. Most importantly, 15% of the patients harbored actionable mutations. Conclusions: Our findings show the feasibility of an NGS approach using both surgical specimens and cytologic samples. The model proposed in this study can be included successfully in the clinical setting for comprehensive molecular profiling of all PDAC patients irrespective of their surgical eligibility.
MeSH term(s)	Humans ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/surgery ; Adenocarcinoma/diagnosis ; Adenocarcinoma/genetics ; Adenocarcinoma/surgery ; Endoscopic Ultrasound-Guided Fine Needle Aspiration ; Carcinoma, Pancreatic Ductal/diagnosis ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/surgery ; Pancreatic Neoplasms
Language	English
Publishing date	2022-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2119789-1
ISSN	1542-7714 ; 1542-3565
ISSN (online)	1542-7714
ISSN	1542-3565
DOI	10.1016/j.cgh.2022.10.014
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