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Article: Editorial: Revisiting seed and soil: A new approach to target hibernating dormant tumor cells.

Santiago-Gómez, Angélica / Barkan, Dalit / Chambers, Ann F

2023 Volume 13, Page(s) 1126924

Language	English
Publishing date	2023-01-30
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1126924
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Article ; Online: Dormant disseminated tumor cells and cancer stem/progenitor-like cells: Similarities and opportunities.

Hen, Omri / Barkan, Dalit

Seminars in cancer biology

2019 Volume 60, Page(s) 157–165

Abstract: Distant recurrences occurring years after removal of the primary tumor arise from disseminated tumor cells (DTCs) that lie dormant (quiescent/asymptomatic) until they emerge to overt metastases. These quiescent DTCs are resistant to conventional ... ...

Abstract	Distant recurrences occurring years after removal of the primary tumor arise from disseminated tumor cells (DTCs) that lie dormant (quiescent/asymptomatic) until they emerge to overt metastases. These quiescent DTCs are resistant to conventional treatments. Hence, to date there is no available treatment which targets dormant DTCs before they form overt metastases. Therefore, understanding the biology of dormant DTCs and the mechanisms of their reactivation is vital in our pursuit to develop therapies to prevent cancer from ever recurring. This review will address the striking similarities between the biology of DTCs and the biology of cancer stem cells (CSCs) or CSC-like cells including cancer progenitor-like cells. These similarities are related to intrinsic mechanisms of survival and quiescence, and their cross-talk with mediators, produced in their surrounding niches that may support either dormancy or outgrowth. Unraveling these similarities may provide us with exciting opportunities to either mitigate the survival of residing dormant DTCs/CSCs or maintain them in a dormant state. Whether the stemness properties of CSCs/cancer progenitor-like cells already comprising the recurring tumor can be exploited in order to differentiate them, and thus promote their dormancy, will be explored as well. Overall, these emerging concepts may provide us with new opportunities to prevent lethal recurrences.
MeSH term(s)	Animals ; Cell Cycle ; Disease Susceptibility ; Humans ; Neoplasm, Residual ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Phenotype ; Recurrence ; Signal Transduction ; Tumor Microenvironment
Language	English
Publishing date	2019-09-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2019.09.002
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Article: EMT and Stemness in Tumor Dormancy and Outgrowth: Are They Intertwined Processes?

Weidenfeld, Keren / Barkan, Dalit

Frontiers in oncology

2018 Volume 8, Page(s) 381

Abstract: Metastases are the major cause of cancer patients' mortality and can occur years and even decades following apparently successful treatment of the primary tumor. Early dissemination of cancer cells, followed by a protracted period of dormancy at distant ... ...

Abstract	Metastases are the major cause of cancer patients' mortality and can occur years and even decades following apparently successful treatment of the primary tumor. Early dissemination of cancer cells, followed by a protracted period of dormancy at distant sites, has been recently recognized as the clinical explanation for this very-long latency. The mechanisms that govern tumor dormancy at distant sites and their reactivation to proliferating metastases are just beginning to be unraveled. Tumor cells, that survive the immune surveillance and hemodynamic forces along their journey in the circulation and successfully colonize and adopt to the new and "hostile" microenvironment and survive in a quiescent dormant state for years before emerging to proliferative state, must display high plasticity. Here we will discuss whether the plasticity of dormant tumor cells is required for their long-term survival and outgrowth. Specifically, we will focus on whether epithelial mesenchymal transition and acquisition of stem-like properties can dictate their quiescent and or their proliferative fate. Deeper understanding of these intertwining processes may facilitate in the future the development of novel therapies.
Language	English
Publishing date	2018-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2018.00381
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Article: Innovative Approaches in the Battle Against Cancer Recurrence: Novel Strategies to Combat Dormant Disseminated Tumor Cells.

Sauer, Scott / Reed, Damon R / Ihnat, Michael / Hurst, Robert E / Warshawsky, David / Barkan, Dalit

Frontiers in oncology

2021 Volume 11, Page(s) 659963

Abstract: Cancer recurrence remains a great fear for many cancer survivors following their initial, apparently successful, therapy. Despite significant improvement in the overall survival of many types of cancer, metastasis accounts for ~90% of all cancer ... ...

Abstract	Cancer recurrence remains a great fear for many cancer survivors following their initial, apparently successful, therapy. Despite significant improvement in the overall survival of many types of cancer, metastasis accounts for ~90% of all cancer mortality. There is a growing understanding that future therapeutic practices must accommodate this unmet medical need in preventing metastatic recurrence. Accumulating evidence supports dormant disseminated tumor cells (DTCs) as a source of cancer recurrence and recognizes the need for novel strategies to target these tumor cells. This review presents strategies to target dormant quiescent DTCs that reside at secondary sites. These strategies aim to prevent recurrence by maintaining dormant DTCs at bay, or eradicating them. Various approaches are presented, including: reinforcing the niche where dormant DTCs reside in order to keep dormant DTCs at bay; promoting cell intrinsic mechanisms to induce dormancy; preventing the engagement of dormant DTCs with their supportive niche in order to prevent their reactivation; targeting cell-intrinsic mechanisms mediating long-term survival of dormant DTCs; sensitizing dormant DTCs to chemotherapy treatments; and, inhibiting the immune evasion of dormant DTCs, leading to their demise. Various therapeutic approaches, some of which utilize drugs that are already approved, or have been tested in clinical trials and may be considered for repurposing, will be discussed. In addition, clinical evidence for the presence of dormant DTCs will be reviewed, along with potential prognostic biomarkers to enable the identification and stratification of patients who are at high risk of recurrence, and who could benefit from novel dormant DTCs targeting therapies. Finally, we will address the shortcomings of current trial designs for determining activity against dormant DTCs and provide novel approaches.
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.659963
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Article: Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis.

Koons, Natalie / Amato, Nicole / Sauer, Scott / Warshawsky, David / Barkan, Dalit / Khanna, Chand

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 10

Abstract: Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To ... ...

Abstract	Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.
Language	English
Publishing date	2021-09-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14100971
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Article ; Online: Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment.

Dinca, Simion C / Greiner, Daniel / Weidenfeld, Keren / Bond, Laura / Barkan, Dalit / Jorcyk, Cheryl L

Breast cancer research : BCR

2021 Volume 23, Issue 1, Page(s) 56

Abstract: Background: Invasive ductal carcinoma (IDC) is a serious problem for patients as it metastasizes, decreasing 5-year patient survival from > 95 to ~ 27%. The breast tumor microenvironment (TME) is often saturated with proinflammatory cytokines, such as ... ...

Abstract	Background: Invasive ductal carcinoma (IDC) is a serious problem for patients as it metastasizes, decreasing 5-year patient survival from > 95 to ~ 27%. The breast tumor microenvironment (TME) is often saturated with proinflammatory cytokines, such as oncostatin M (OSM), which promote epithelial-to-mesenchymal transitions (EMT) in IDC and increased metastasis. The extracellular matrix (ECM) also plays an important role in promoting invasive and metastatic potential of IDC. Specifically, the reorganization and alignment of collagen fibers in stromal ECM leads to directed tumor cell motility, which promotes metastasis. Lysyl oxidase like-2 (LOXL2) catalyzes ECM remodeling by crosslinking of collagen I in the ECM. We propose a novel mechanism whereby OSM induces LOXL2 expression, mediating stromal ECM remodeling of the breast TME. Methods: Bioinformatics was utilized to determine survival and gene correlation in patients. IDC cell lines were treated with OSM (also IL-6, LIF, and IL-1β) and analyzed for LOXL2 expression by qRT-PCR and immunolabelling techniques. Collagen I contraction assays, 3D invasion assays, and confocal microscopy were performed with and without LOXL2 inhibition to determine the impact of OSM-induced LOXL2 on the ECM. Results: Our studies demonstrate that IDC patients with high LOXL2 and OSM co-expression had worse rates of metastasis-free survival than those with high levels of either, individually, and LOXL2 expression is positively correlated to OSM/OSM receptor (OSMR) expression in IDC patients. Furthermore, human IDC cells treated with OSM resulted in a significant increase in LOXL2 mRNA, which led to upregulated protein expression of secreted, glycosylated, and enzymatically active LOXL2. The expression of LOXL2 in IDC cells did not affect OSM-promoted EMT, and LOXL2 was localized to the cytoplasm and/or secreted. OSM-induced LOXL2 promoted an increase in ECM collagen I fiber crosslinking, which led to significant fiber alignment between cells and increased IDC cell invasion. Conclusions: Aligned collagen fibers in the ECM provide pathways for tumor cells to migrate more easily through the stroma to nearby vasculature and tissue. These results provide a new paradigm through which proinflammatory cytokine OSM promotes tumor progression. Understanding the nuances in IDC metastasis will lead to better potential therapeutics to combat against the possibility.
MeSH term(s)	Amino Acid Oxidoreductases/genetics ; Amino Acid Oxidoreductases/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Carcinoma, Ductal, Breast/genetics ; Carcinoma, Ductal, Breast/metabolism ; Carcinoma, Ductal, Breast/pathology ; Cell Line, Tumor ; Collagen Type I/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Extracellular Matrix/metabolism ; Female ; Glycosylation ; Humans ; Inflammation ; Neoplasm Metastasis ; Oncostatin M/genetics ; Oncostatin M/metabolism ; Oncostatin M/pharmacology ; Oncostatin M Receptor beta Subunit/genetics ; Oncostatin M Receptor beta Subunit/metabolism ; Prognosis ; Signal Transduction ; Tumor Microenvironment ; Up-Regulation/genetics
Chemical Substances	Collagen Type I ; OSM protein, human ; OSMR protein, human ; Oncostatin M Receptor beta Subunit ; Oncostatin M (106956-32-5) ; Amino Acid Oxidoreductases (EC 1.4.-) ; LOXL2 protein, human (EC 1.4.3.-)
Language	English
Publishing date	2021-05-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-021-01430-x
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Article ; Online: Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis

Natalie Koons / Nicole Amato / Scott Sauer / David Warshawsky / Dalit Barkan / Chand Khanna

Pharmaceuticals, Vol 14, Iss 971, p

2021 Volume 971

Abstract	Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.
Keywords	osteosarcoma ; metastatic endurance ; small molecule inhibitors ; oclacitinib ; regorafenib ; saracatinib ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Telemedicine Versus Traditional In-Person Consultations: Comparison of Patient Satisfaction Rates.

Hamiel, Uri / Eshel Fuhrer, Audelia / Landau, Nitsan / Reches, Adi / Ponger, Penina / Elhanan, Emil / Tali, Barkan / Barel, Dalit / Simchoni, Sharon / Ofen Glassner, Vered / Botvinik, Adi / Levin, Shir / Baris Feldman, Hagit / Marom, Daphna

Telemedicine journal and e-health : the official journal of the American Telemedicine Association

2023 Volume 30, Issue 4, Page(s) 1013–1019

Abstract: Introduction: ...

Abstract	Introduction:
MeSH term(s)	Adult ; Humans ; Child ; Patient Satisfaction ; Cross-Sectional Studies ; Telemedicine/methods ; Referral and Consultation ; Genetic Counseling
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2035659-6
ISSN	1556-3669 ; 1530-5627
ISSN (online)	1556-3669
ISSN	1530-5627
DOI	10.1089/tmj.2023.0273
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Zs.A 4576: Show issues

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Article ; Online: Corrigendum: Transcriptomic Analysis of Monocyte-Derived Non-Phagocytic Macrophages Favors a Role in Limiting Tissue Repair and Fibrosis.

Butenko, Sergei / Satyanarayanan, Senthil K / Assi, Simaan / Schif-Zuck, Sagie / Barkan, Dalit / Sher, Noa / Ariel, Amiram

Frontiers in immunology

2020 Volume 11, Page(s) 1003

Abstract: This corrects the article DOI: 10.3389/fimmu.2020.00405.]. ...

Abstract	[This corrects the article DOI: 10.3389/fimmu.2020.00405.].
Language	English
Publishing date	2020-05-20
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01003
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Article: β1-integrin: a potential therapeutic target in the battle against cancer recurrence.

Barkan, Dalit / Chambers, Ann F

Clinical cancer research : an official journal of the American Association for Cancer Research

2011 Volume 17, Issue 23, Page(s) 7219–7223

Abstract: Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant ... ...

Abstract	Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant metastases, in some cases many years after apparently successful primary treatment. Significant tumor dormancy has been documented in several cancers, such as breast, melanoma, and renal cancer. Tumor dormancy has long been recognized as an important problem in management of cancer patients. Recent work has clarified biologic aspects of tumor dormancy and has shown that dormant tumor cells may be resistant to cytotoxic chemotherapy and radiation. This work has led to recognition of a key role for β1-integrin in regulating the switch from a dormant state to active proliferation and metastasis. Here we discuss the role of β1-integrin and its signaling partners in regulating the dormant phenotype. We also consider possible therapeutic approaches, such as small molecules or antibodies (ATN-161, volociximab, and JSM6427), directed against β1-integrin signaling to target dormant cancer cells and to prevent metastatic recurrence.
MeSH term(s)	Combined Modality Therapy ; Humans ; Integrin beta1/metabolism ; Molecular Targeted Therapy ; Neoplasm Metastasis/drug therapy ; Neoplasm Metastasis/radiotherapy ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/prevention & control ; Neoplasm Recurrence, Local/radiotherapy ; Neoplasms/drug therapy ; Neoplasms/radiotherapy ; Neoplasms/therapy ; Signal Transduction
Chemical Substances	Integrin beta1
Language	English
Publishing date	2011-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-11-0642
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