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Article ; Online: A new sophistication for breast cancer PDXs.

Portman, Neil / Lim, Elgene

Nature cancer

2022 Volume 3, Issue 2, Page(s) 138–140

MeSH term(s)	Animals ; Breast Neoplasms ; Disease Models, Animal ; Female ; Humans ; Xenograft Model Antitumor Assays
Language	English
Publishing date	2022-02-24
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-021-00328-z
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Article: MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

Portman, Neil / Chen, Julia / Lim, Elgene

Frontiers in oncology

2021 Volume 11, Page(s) 777867

Abstract: With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for ... ...

Abstract	With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2
Language	English
Publishing date	2021-11-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.777867
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Article: Epigenetic Therapies and Biomarkers in Breast Cancer.

Brown, Lauren Julia / Achinger-Kawecka, Joanna / Portman, Neil / Clark, Susan / Stirzaker, Clare / Lim, Elgene

Cancers

2022 Volume 14, Issue 3

Abstract: Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, ...

Abstract	Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, with limited supportive data in solid malignancies. The most studied epigenetic therapies in breast cancer are those that target DNA methylation and histone modification; however, none have been approved for routine clinical use. The majority of pre-clinical and clinical studies have focused on triple negative breast cancer (TNBC) and hormone-receptor positive breast cancer. Even though the use of epigenetic therapies alone in the treatment of breast cancer has not shown significant clinical benefit, these therapies show most promise in use in combinations with other treatments. With improving technologies available to study the epigenetic landscape in cancer, novel epigenetic alterations are increasingly being identified as potential biomarkers of response to conventional and epigenetic therapies. In this review, we describe epigenetic targets and potential epigenetic biomarkers in breast cancer, with a focus on clinical trials of epigenetic therapies. We describe alterations to the epigenetic landscape in breast cancer and in treatment resistance, highlighting mechanisms and potential targets for epigenetic therapies. We provide an updated review on epigenetic therapies in the pre-clinical and clinical setting in breast cancer, with a focus on potential real-world applications. Finally, we report on the potential value of epigenetic biomarkers in diagnosis, prognosis and prediction of response to therapy, to guide and inform the clinical management of breast cancer patients.
Language	English
Publishing date	2022-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14030474
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Article ; Online: Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues.

Everett, James / Brooks, Jake / Tjendana Tjhin, Vindy / Lermyte, Frederik / Hands-Portman, Ian / Plascencia-Villa, Germán / Perry, George / Sadler, Peter J / O'Connor, Peter B / Collingwood, Joanna F / Telling, Neil D

ACS chemical neuroscience

2024 Volume 15, Issue 7, Page(s) 1469–1483

Abstract: The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of ... ...

Abstract	The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C-H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism ; Brain/metabolism ; Iron/metabolism ; Calcium/metabolism
Chemical Substances	Amyloid beta-Peptides ; Iron (E1UOL152H7) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.3c00756
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Article ; Online: Triple combination targeting PI3K, ER, and CDK4/6 inhibits growth of ER-positive breast cancer resistant to fulvestrant and CDK4/6 or PI3K inhibitor.

Karimi, Leena / Alves, Carla L / Terp, Mikkel G / Tuttolomondo, Martina / Portman, Neil / Ehmsen, Sidse / Johansen, Lene E / Bak, Martin / Lim, Elgene / Ditzel, Henrik J

Cancer communications (London, England)

2023 Volume 43, Issue 6, Page(s) 720–725

MeSH term(s)	Humans ; Female ; Breast Neoplasms ; Fulvestrant ; Phosphatidylinositol 3-Kinases ; Cell Line, Tumor ; Signal Transduction ; Cyclin-Dependent Kinase 4
Chemical Substances	Fulvestrant (22X328QOC4) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2023-04-26
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ISSN	2523-3548
ISSN (online)	2523-3548
DOI	10.1002/cac2.12425
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Article ; Online: Edoxaban for Thromboembolism Prevention in Pediatric Patients With Cardiac Disease.

Portman, Michael A / Jacobs, Jeffrey P / Newburger, Jane W / Berger, Felix / Grosso, Michael A / Duggal, Anil / Tao, Ben / Goldenberg, Neil A

Journal of the American College of Cardiology

2022 Volume 80, Issue 24, Page(s) 2301–2310

Abstract: Background: Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants ... ...

Abstract	Background: Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants in children. Objectives: The investigators aimed to obtain safety and efficacy data for edoxaban in children. Methods: We performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients <18 years of age with cardiac disease (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease] trial). Patients were randomized 2:1 to age- and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis. Both groups could continue in an open-label edoxaban extension arm through 1 year. The primary endpoint was adjudicated clinically relevant bleeding (CRB). The main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis. Results: The modified intention-to-treat cohort included 167 children. One patient per group experienced a nonmajor CRB in the main period. Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC. One SOC patient experienced 2 TE events (DVT with PE). Among 147 children in the extension, 1 CRB event (0.7%) and 4 TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions). Conclusions: Edoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of CRB and TEs with advantages of once daily dosing and infrequent monitoring requirement. (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots] (Thrombotic Events) in Children at Risk Because of Cardiac Disease trial; NCT03395639).
MeSH term(s)	Humans ; Child ; Anticoagulants ; Prospective Studies ; Venous Thromboembolism ; Social Group ; Heart Diseases
Chemical Substances	Anticoagulants
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2022.09.031
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Article ; Online: The flagellar contribution to the apical complex: a new tool for the eukaryotic Swiss Army knife?

Portman, Neil / Slapeta, Jan

Trends in parasitology

2014 Volume 30, Issue 2, Page(s) 58–64

Abstract: Apicomplexa are an ancient group of single-celled pathogens of humans and animals that include the etiological agents of such devastating plagues as malaria, toxoplasmosis, and coccidiosis. The defining feature of the Apicomplexa is the apical complex, ... ...

Abstract	Apicomplexa are an ancient group of single-celled pathogens of humans and animals that include the etiological agents of such devastating plagues as malaria, toxoplasmosis, and coccidiosis. The defining feature of the Apicomplexa is the apical complex, the invasion machinery used to gain access to host cells. Evidence gathered from apicomplexans and their closest relatives argues that the apical complex is an extreme example of flagellum adaptability. The value of non-apicomplexan models, such as Chromera velia, is considered in an effort to understand the modern apical complex. The origin of the apical complex is unknown, but recent evidence points to a remarkable contribution from the flagellum to its evolution.
MeSH term(s)	Animals ; Apicomplexa/cytology ; Apicomplexa/physiology ; Biological Evolution
Language	English
Publishing date	2014-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2036227-4
ISSN	1471-5007 ; 1471-4922
ISSN (online)	1471-5007
ISSN	1471-4922
DOI	10.1016/j.pt.2013.12.006
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Article ; Online: Identification of paralogous life-cycle stage specific cytoskeletal proteins in the parasite Trypanosoma brucei.

Portman, Neil / Gull, Keith

PloS one

2014 Volume 9, Issue 9, Page(s) e106777

Abstract: The life cycle of the African trypanosome Trypanosoma brucei, is characterised by a transition between insect and mammalian hosts representing very different environments that present the parasite with very different challenges. These challenges are met ... ...

Abstract	The life cycle of the African trypanosome Trypanosoma brucei, is characterised by a transition between insect and mammalian hosts representing very different environments that present the parasite with very different challenges. These challenges are met by the expression of life-cycle stage-specific cohorts of proteins, which function in systems such as metabolism and immune evasion. These life-cycle transitions are also accompanied by morphological rearrangements orchestrated by microtubule dynamics and associated proteins of the subpellicular microtubule array. Here we employed a gel-based comparative proteomic technique, Difference Gel Electrophoresis, to identify cytoskeletal proteins that are expressed differentially in mammalian infective and insect form trypanosomes. From this analysis we identified a pair of novel, paralogous proteins, one of which is expressed in the procyclic form and the other in the bloodstream form. We show that these proteins, CAP51 and CAP51V, localise to the subpellicular corset of microtubules and are essential for correct organisation of the cytoskeleton and successful cytokinesis in their respective life cycle stages. We demonstrate for the first time redundancy of function between life-cycle stage specific paralogous sets in the cytoskeleton and reveal modification of cytoskeletal components in situ prior to their removal during differentiation from the bloodstream form to the insect form. These specific results emphasise a more generic concept that the trypanosome genome encodes a cohort of cytoskeletal components that are present in at least two forms with life-cycle stage-specific expression.
MeSH term(s)	Animals ; Cytokinesis ; Cytoskeletal Proteins/metabolism ; Insecta/parasitology ; Life Cycle Stages ; Microtubules/metabolism ; Proteomics ; Protozoan Proteins/metabolism ; Sequence Homology, Amino Acid ; Trypanosoma brucei brucei/cytology ; Trypanosoma brucei brucei/growth & development ; Trypanosoma brucei brucei/metabolism ; Trypanosoma brucei brucei/physiology
Chemical Substances	Cytoskeletal Proteins ; Protozoan Proteins
Language	English
Publishing date	2014-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0106777
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Article ; Online: Molecular Biomarkers for Contemporary Therapies in Hormone Receptor-Positive Breast Cancer.

Freelander, Allegra / Brown, Lauren J / Parker, Andrew / Segara, Davendra / Portman, Neil / Lau, Brandon / Lim, Elgene

Genes

2021 Volume 12, Issue 2

Abstract: Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased ... ...

Abstract	Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased use of targeted therapies has changed the natural history of HR+ breast cancers, with the emergence of new escape mechanisms leading to the inevitable progression of disease in patients with advanced cancers. The identification of new predictive and pharmacodynamic biomarkers to current standard-of-care therapies and discovery of new therapies is an evolving and urgent clinical challenge in this setting. While traditional, routinely measured biomarkers such as estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic tests have emerged as a useful adjunct prognostication tool and guide the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify
MeSH term(s)	Biomarkers, Tumor/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Class I Phosphatidylinositol 3-Kinases/genetics ; Estrogen Receptor alpha/genetics ; Female ; Hormones/therapeutic use ; Humans ; Neoplasm Metastasis ; Oncogene Protein v-akt/genetics ; Prognosis ; Receptor, ErbB-2/genetics ; Receptors, Estrogen/genetics ; Receptors, Progesterone/genetics
Chemical Substances	Biomarkers, Tumor ; ESR1 protein, human ; Estrogen Receptor alpha ; Hormones ; Receptors, Estrogen ; Receptors, Progesterone ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Oncogene Protein v-akt (EC 2.7.11.1)
Language	English
Publishing date	2021-02-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12020285
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Article: The flagellar contribution to the apical complex: a new tool for the eukaryotic Swiss Army knife?

Portman, Neil / Jan Šlapeta

Trends in parasitology. 2014 Feb., v. 30, no. 2

2014

Abstract	Apicomplexa are an ancient group of single-celled pathogens of humans and animals that include the etiological agents of such devastating plagues as malaria, toxoplasmosis, and coccidiosis. The defining feature of the Apicomplexa is the apical complex, the invasion machinery used to gain access to host cells. Evidence gathered from apicomplexans and their closest relatives argues that the apical complex is an extreme example of flagellum adaptability. The value of non-apicomplexan models, such as Chromera velia, is considered in an effort to understand the modern apical complex. The origin of the apical complex is unknown, but recent evidence points to a remarkable contribution from the flagellum to its evolution.
Keywords	flagellum ; humans ; malaria ; Miozoa ; models ; pathogens ; toxoplasmosis
Language	English
Dates of publication	2014-02
Size	p. 58-64.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2036227-4
ISSN	1471-5007 ; 1471-4922
ISSN (online)	1471-5007
ISSN	1471-4922
DOI	10.1016/j.pt.2013.12.006
Database	NAL-Catalogue (AGRICOLA)

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