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Article ; Online: The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer

Gulnihal Ozcan

Frontiers in Cell and Developmental Biology, Vol

Future directions for therapeutic targeting

2023 Volume 11

Abstract: Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in ... ...

Abstract	Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.
Keywords	hypoxia-inducible factor-1α ; gastric cancer ; stemness ; chemoresistance ; deregulated signaling ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting.

Ozcan, Gulnihal

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1082057

Abstract	Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.
Language	English
Publishing date	2023-02-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1082057
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: PTCH1

Ozcan, Gulnihal

Frontiers in oncology

2023 Volume 13, Page(s) 1216438

Abstract: Introduction: Endeavors in the molecular characterization of breast cancer opened the doors to endocrine therapies in ER+/HER2- breast cancer, increasing response rates substantially. Despite that, taxane-based neoadjuvant chemotherapy is still a ... ...

Abstract	Introduction: Endeavors in the molecular characterization of breast cancer opened the doors to endocrine therapies in ER+/HER2- breast cancer, increasing response rates substantially. Despite that, taxane-based neoadjuvant chemotherapy is still a cornerstone for achieving breast-conserving surgery and complete tumor resection in locally advanced cancers with high recurrence risk. Nonetheless, the rate of chemoresistance is high, and deselecting patients who will not benefit from chemotherapy is a significant task to prevent futile toxicities. Several multigene assays are being used to guide decisions on chemotherapy. However, their development as prognostic assays but not predictive assays limits predictive strength, leading to discordant results. Moreover, high costs impediment their use in developing countries. For global health equity, robust predictors that can be cost-effectively incorporated into routine clinical management are essential. Methods: In this study, we comprehensively analyzed 5 GEO datasets, 2 validation sets, and The Cancer Genome Atlas breast cancer data to identify predictors of resistance to taxane-based neoadjuvant therapy in ER+/HER2- breast cancer using efficient bioinformatics algorithms. Results: Gene expression and gene set enrichment analysis of 5 GEO datasets revealed the upregulation of 63 genes and the enrichment of CTNNB1-related oncogenic signatures in non-responsive patients. We validated the upregulation and predictive strength of 18 genes associated with resistance in the validation cohort, all exhibiting higher predictive powers for residual disease and higher specificities for ER+/HER2- breast cancers compared to one of the benchmark multi-gene assays. Cox Proportional Hazards Regression in three different treatment arms (neoadjuvant chemotherapy, endocrine therapy, and no systemic treatment) in a second comprehensive validation cohort strengthened the significance of Discussion: Our results strongly suggest that PTCH1 and CTNNB1 can be used as robust and cost-effective predictors in developing countries to guide decisions on chemotherapy in ER +/HER2- breast cancer patients with a high risk of recurrence. The dual function of PTCH1 as a multidrug efflux pump and a hedgehog receptor, and the active involvement of CTNNB1 in breast cancer strongly indicate that
Language	English
Publishing date	2023-08-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1216438
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Article ; Online: SCUBE2 as a Marker of Resistance to Taxane-based Neoadjuvant Chemotherapy and a Potential Therapeutic Target in Breast Cancer

Gülnihal Özcan

European Journal of Breast Health, Vol 19, Iss 1, Pp 45-

2023 Volume 54

Abstract: Objective:Taxane-based neoadjuvant chemotherapy is the most common neoadjuvant approach in breast cancer, especially in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes. However, chemoresistance is a problem in many ... ...

Abstract	Objective:Taxane-based neoadjuvant chemotherapy is the most common neoadjuvant approach in breast cancer, especially in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes. However, chemoresistance is a problem in many patients, and success rates are low in estrogen receptor (ER)-positive breast cancer. The aim of this study was to identify predictive markers for resistance to taxane-based therapy, which may have a potential as therapeutic targets in breast cancer.Materials and Methods:Three comprehensive breast cancer Gene Expression Omnibus datasets were analyzed to identify differentially expressed genes (DEGs) in breast cancer patients resistant to taxane-based neoadjuvant chemotherapy. Functional annotation clustering and enrichment analysis were performed on the DEGs list. A protein-protein interaction network was established with the upregulated genes. The predictive value and the differential expression of the central genes were validated in the extensive ROC Plotter database.Results:Seventeen upregulated genes were found which were associated with resistance to taxane-based neoadjuvant therapy and high connectivity in the network analysis. ESR1, CCND1, and SCUBE2 emerged as the top three key genes associated with resistance. SCUBE2 displayed a high predictive power comparable to ESR1, and better than CCND1, the two commonly accepted markers. The predictive ability of SCUBE2 was higher in ER-positive and HER2-positive breast cancers.Conclusion:These results suggest that SCUBE2 may be used as a predictive marker to guide decisions on neoadjuvant therapy. Emerging evidence about the role of SCUBE2 as a coreceptor involved in tumor progression and angiogenesis also suggests SCUBE2 as a potential therapeutic target. These points should be investigated in further studies.
Keywords	breast cancer ; neoadjuvant chemotherapy ; chemoresistance ; biomarkers ; bioinformatics ; scube2 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Galenos Publishing House
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.

Ozmen, Ece / Demir, Tevriz Dilan / Ozcan, Gulnihal

Frontiers in molecular biosciences

2024 Volume 11, Page(s) 1340124

Abstract: Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor ... ...

Abstract	Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.
Language	English
Publishing date	2024-03-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2024.1340124
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Article: The HIF-1α as a Potent Inducer of the Hallmarks in Gastric Cancer.

Ucaryilmaz Metin, Cemre / Ozcan, Gulnihal

Cancers

2022 Volume 14, Issue 11

Abstract: Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxia-inducible factor-1α (HIF-1α) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1α potently ... ...

Abstract	Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxia-inducible factor-1α (HIF-1α) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1α potently induces sustained growth factor signaling, angiogenesis, epithelial-mesenchymal transition, and replicative immortality. Hypoxia leads to the selection of cancer cells that evade growth suppressors or apoptotic triggers and deregulates cellular energetics. HIF-1α is also associated with genetic instability, tumor-promoting inflammation, and escape from immunity. Therefore, HIF-1α may be an important therapeutic target in cancer. Despite that, the drug market lacks safe and efficacious anti-HIF-1α molecules, raising the quest for fully unveiling the complex interactome of HIF-1α in cancer to discover more effective strategies. The knowledge gap is even wider in gastric cancer, where the number of studies on hypoxia is relatively low compared to other well-dissected cancers. A comprehensive review of the molecular mechanisms by which HIF-1α induces gastric cancer hallmarks could provide a broad perspective to the investigators and reveal missing links to explore in future studies. Thus, here we review the impact of HIF-1α on the cancer hallmarks with a specific focus on gastric cancer.
Language	English
Publishing date	2022-05-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14112711
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Article ; Online: Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer.

Ucaryilmaz Metin, Cemre / Ozcan, Gulnihal

BMC cancer

2022 Volume 22, Issue 1, Page(s) 692

Abstract: Background: Gastric cancer is one of the deadliest cancers, currently available therapies have limited success. Cancer-associated fibroblasts (CAFs) are pivotal cells in the stroma of gastric tumors posing a great risk for progression and ... ...

Abstract	Background: Gastric cancer is one of the deadliest cancers, currently available therapies have limited success. Cancer-associated fibroblasts (CAFs) are pivotal cells in the stroma of gastric tumors posing a great risk for progression and chemoresistance. The poor prognostic signature for CAFs is not clear in gastric cancer, and drugs that target CAFs are lacking in the clinic. In this study, we aim to identify a poor prognostic gene signature for CAFs, targeting which may increase the therapeutic success in gastric cancer. Methods: We analyzed four GEO datasets with a network-based approach and validated key CAF markers in The Cancer Genome Atlas (TCGA) and The Asian Cancer Research Group (ACRG) cohorts. We implemented stepwise multivariate Cox regression guided by a pan-cancer analysis in TCGA to identify a poor prognostic gene signature for CAF infiltration in gastric cancer. Lastly, we conducted a database search for drugs targeting the signature genes. Results: Our study revealed the COL1A1, COL1A2, COL3A1, COL5A1, FN1, and SPARC as the key CAF markers in gastric cancer. Analysis of the TCGA and ACRG cohorts validated their upregulation and poor prognostic significance. The stepwise multivariate Cox regression elucidated COL1A1 and COL5A1, together with ITGA4, Emilin1, and TSPAN9 as poor prognostic signature genes for CAF infiltration. The search on drug databases revealed collagenase clostridium histolyticum, ocriplasmin, halofuginone, natalizumab, firategrast, and BIO-1211 as the potential drugs for further investigation. Conclusions: Our study demonstrated the central role of extracellular matrix components secreted and remodeled by CAFs in gastric cancer. The gene signature we identified in this study carries high potential as a predictive tool for poor prognosis in gastric cancer patients. Elucidating the mechanisms by which the signature genes contribute to poor patient outcomes can lead to the discovery of more potent molecular-targeted agents and increase the therapeutic success in gastric cancer.
MeSH term(s)	Cancer-Associated Fibroblasts/pathology ; Computational Biology ; Humans ; Prognosis ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/genetics ; Stomach Neoplasms/pathology
Language	English
Publishing date	2022-06-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-022-09736-5
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Article: Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

Leylek, Ozen / Honeywell, Megan E / Lee, Michael J / Hemann, Michael T / Ozcan, Gulnihal

bioRxiv : the preprint server for biology

2023

Abstract: The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the ... ...

Abstract	The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib's off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.
Language	English
Publishing date	2023-11-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.07.561351
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Article ; Online: Extracranial transport of brain lymphatics via cranial nerve in human.

Çavdar, Safiye / Altınöz, Damlasu / Dilan Demir, Tevriz / Ali Gürses, İlke / Özcan, Gülnihal

Neuroscience letters

2024 Volume 827, Page(s) 137737

Abstract: Extracranial waste transport from the brain interstitial fluid to the deep cervical lymph node (dCLN) is not extensively understood. The present study aims to show the cranial nerves that have a role in the transport of brain lymphatics vessels (LVs), ... ...

Abstract	Extracranial waste transport from the brain interstitial fluid to the deep cervical lymph node (dCLN) is not extensively understood. The present study aims to show the cranial nerves that have a role in the transport of brain lymphatics vessels (LVs), their localization, diameter, and number using podoplanin (PDPN) and CD31 immunohistochemistry (IHC) and Western blotting. Cranial nerve samples from 6 human cases (3 cadavers, and 3 autopsies) were evaluated for IHC and 3 autopsies for Western blotting. The IHC staining showed LVs along the optic, olfactory, oculomotor, trigeminal, facial, glossopharyngeal, accessory, and vagus nerves. However, no LVs present along the trochlear, abducens, vestibulocochlear, and hypoglossal nerves. The LVs were predominantly localized at the endoneurium of the cranial nerve that has motor components, and LVs in the cranial nerves that had sensory components were present in all 3 layers. The number of LVs accompanying the olfactory, optic, and trigeminal nerves was classified as numerous; oculomotor, glossopharyngeal, vagus, and accessory was moderate; and facial nerves was few. The largest diameter of LVs was in the epineurium and the smallest one was in the endoneurium. The majority of Western blotting results correlated with the IHC. The present findings suggest that specific cranial nerves with variable quantities provide a pathway for the transport of wastes from the brain to dCLN. Thus, the knowledge of the transport of brain lymphatics along cranial nerves may help understand the pathophysiology of various neurological diseases.
MeSH term(s)	Humans ; Cranial Nerves/physiology ; Brain ; Vagus Nerve/physiology ; Facial Nerve/physiology ; Skull ; Trigeminal Nerve/physiology ; Hypoglossal Nerve ; Glossopharyngeal Nerve/physiology ; Oculomotor Nerve ; Abducens Nerve
Language	English
Publishing date	2024-03-20
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2024.137737
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Article: Resorufin Enters the Photodynamic Therapy Arena: A Monoamine Oxidase Activatable Agent for Selective Cytotoxicity.

Almammadov, Toghrul / Atakan, Gizem / Leylek, Ozen / Ozcan, Gulnihal / Gunbas, Gorkem / Kolemen, Safacan

ACS medicinal chemistry letters

2020 Volume 11, Issue 12, Page(s) 2491–2496

Abstract: A red-absorbing, water-soluble, and iodinated resorufin derivative ( ...

Abstract	A red-absorbing, water-soluble, and iodinated resorufin derivative (
Language	English
Publishing date	2020-11-23
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.0c00484
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