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Article: Role of PLK1/NUMB/NOTCH in epithelial-mesenchymal transition in human melanoma.

Chhabra, Gagan / Singh, Chandra K / Ndiaye, Mary A / Su, Shengqin / Shirley, Carl A / Ahmad, Nihal

NPJ precision oncology

2024 Volume 8, Issue 1, Page(s) 6

Abstract: Polo-like kinase 1 (PLK1), a serine/threonine kinase, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1, NUMB, ... ...

Abstract	Polo-like kinase 1 (PLK1), a serine/threonine kinase, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1, NUMB, and NOTCH signaling in epithelial-mesenchymal transition (EMT) in melanoma progression is unclear. In this study, Affymetrix microarray analysis was performed to determine differentially expressed genes following shRNA-mediated knockdown of PLK1 in human melanoma cells that showed significant modulations in EMT and metastasis-related genes. Using multiple PLK1-modulated melanoma cell lines, we found that PLK1 is involved in the regulation of cell migration, invasion, and EMT via its kinase activity and NOTCH activation. In vitro kinase assay and mass spectrometry analysis demonstrated a previously unknown PLK1 phosphorylation site (Ser413) on NUMB. Overexpression of non-phosphorylatable (S413A) and phosphomimetic (S413D) mutants of NUMB in melanoma cells implicated the involvement of NUMB-S413 phosphorylation in cell migration and invasion, which was independent of NOTCH activation. To determine the clinical relevance of these findings, immunohistochemistry was performed using melanoma tissue microarray, which indicated a strong positive correlation between PLK1 and N-cadherin, a protein required for successful EMT. These findings were supported by TCGA analysis, where expression of high PLK1 with low NUMB or high NOTCH or N-cadherin showed a significant decrease in survival of melanoma patients. Overall, these results suggest a potential role of PLK1 in EMT, migration, and invasion of melanoma cells. Our findings support the therapeutic targeting of PLK1, NUMB, and NOTCH for melanoma management.
Language	English
Publishing date	2024-01-06
Publishing country	England
Document type	Journal Article
ISSN	2397-768X
ISSN	2397-768X
DOI	10.1038/s41698-023-00493-7
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Article: Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter.

Thornton, Jessica / Chhabra, Gagan / Singh, Chandra K / Guzmán-Pérez, Glorimar / Shirley, Carl A / Ahmad, Nihal

Frontiers in oncology

2022 Volume 12, Page(s) 880876

Abstract: Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior ...

Abstract	Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior to the advent of targeted and immunotherapies, metastatic melanoma was considered a death sentence, with less than 5% of patients surviving more than 5 years. With the implementation of immunotherapies, approximately half of patients with metastatic melanoma now survive more than 5 years. Unfortunately, this also means that half of the patients with melanoma do not respond to current therapies and live less than 5 years after diagnosis. One major factor that contributes to lower response in this population is acquired or primary resistance to immunotherapies
Language	English
Publishing date	2022-04-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.880876
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Article: Whole Fruit Phytochemicals Combating Skin Damage and Carcinogenesis.

Mintie, Charlotte A / Singh, Chandra K / Ahmad, Nihal

Translational oncology

2019 Volume 13, Issue 2, Page(s) 146–156

Abstract: Skin is arguably the largest organ of the body and is continuously subjected to intrinsic, extrinsic, and environmental stresses. Therefore, skin developed elaborate mechanisms to maintain homeostasis, including antioxidant, antiinflammatory, and DNA ... ...

Abstract	Skin is arguably the largest organ of the body and is continuously subjected to intrinsic, extrinsic, and environmental stresses. Therefore, skin developed elaborate mechanisms to maintain homeostasis, including antioxidant, antiinflammatory, and DNA damage repair capabilities. However, repeated and excessive stresses can overwhelm these systems, causing serious cutaneous damages, including skin carcinogenesis. Phytonutrients present in the diet possess a myriad of health-promoting effects by protecting skin from damaging free radicals as well as by other mechanisms. Although many chemoprotective phytonutrients have been shown to be efficacious individually, a combination of multiple agents could have synergistic response in curtailing or preventing cutaneous damages. Here, we discuss the benefits of natural amalgamation of phytonutrients in select fruits against skin damage including carcinogenesis. However, a majority of these studies have been done in preclinical models. Therefore, clinical studies are needed to determine the human relevance of the available preclinical data, especially in the human population who are at higher risk for skin cancers (e.g., organ transplant patients). In addition, detailed well-structured preclinical animal studies in the models of high-risk skin carcinogenesis could also be useful toward informing the design for human trials.
Language	English
Publishing date	2019-12-19
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2443840-6
ISSN	1936-5233 ; 1936-5233 ; 1944-7124
ISSN (online)	1936-5233
ISSN	1936-5233 ; 1944-7124
DOI	10.1016/j.tranon.2019.10.014
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Article ; Online: The role of Collagen Triple Helix Repeat Containing 1 (CTHRC1) in cancer development and progression.

Singh, Chandra K / Fernandez, Sofia / Chhabra, Gagan / Zaemisch, Gabriella R / Nihal, Ayaan / Swanlund, Jenna / Ansari, Naveed / Said, Zan / Chang, Hao / Ahmad, Nihal

Expert opinion on therapeutic targets

2024

Abstract: Introduction: Collagen triple helix repeat containing 1 (CTHRC1) is a protein that has been implicated in pro-migratory pathways, arterial tissue-repair processes, and inhibition of collagen deposition via the regulation of multiple signaling cascades. ... ...

Abstract	Introduction: Collagen triple helix repeat containing 1 (CTHRC1) is a protein that has been implicated in pro-migratory pathways, arterial tissue-repair processes, and inhibition of collagen deposition via the regulation of multiple signaling cascades. Studies have also demonstrated an upregulation of CTHRC1 in multiple cancers where it has been linked to enhanced proliferation, invasion, and metastasis. However, the understanding of the exact role and mechanisms of CTHRC1 in cancer is far from complete. Areas covered: This review focuses on analyzing the role of CTHRC1 in cancer as well as its associations with clinicopathologies and cancer-related processes and signaling. We have also summarized the available literature information regarding the role of CTHRC1 in tumor microenvironment and immune signaling. Finally, we have discussed the mechanisms associated with CTHRC1 regulations, and opportunities and challenges regarding the development of CTHRC1 as a potential target for cancer management. Expert opinion: CTHRC1 is a multifaceted protein with critical roles in cancer progression and other pathological conditions. Its association with lower overall survival in various cancers, and impact on the tumor immune microenvironment make it an intriguing target for further research and potential therapeutic interventions in cancer.
Language	English
Publishing date	2024-04-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2055208-7
ISSN	1744-7631 ; 1472-8222
ISSN (online)	1744-7631
ISSN	1472-8222
DOI	10.1080/14728222.2024.2349686
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Article: Dietary Phytochemicals in Zinc Homeostasis: A Strategy for Prostate Cancer Management

Singh, Chandra K. / Chhabra, Gagan / Patel, Arth / Chang, Hao / Ahmad, Nihal

Nutrients. 2021 May 30, v. 13, no. 6

2021

Abstract: Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer ...

Abstract	Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer (PCa), Zn levels are significantly decreased and inversely correlated with disease progression. Ideally, restoration of adequate Zn levels in premalignant/malignant prostate cells could abort prostate malignancy. However, studies have shown that Zn supplementation is not an efficient way to significantly increase Zn concentrations in PCa. Based on a limited number of investigations, the reason for the lower levels of Zn in PCa is believed to be the dysregulation of Zn transporters (especially ZIP and ZnT family of proteins), metallothioneins (for storing and releasing Zn), and their regulators (e.g., Zn finger transcription factor RREB1). Interestingly, the level of Zn in cells has been shown to be modulated by naturally occurring dietary phytochemicals. In this review, we discussed the effect of selected phytochemicals (quercetin, resveratrol, epigallocatechin-3-gallate and curcumin) on Zn functioning and proposes that Zn in combination with specific dietary phytochemicals may lead to enhanced Zn bioaccumulation in the prostate, and therefore, may inhibit PCa.
Keywords	bioaccumulation ; curcumin ; disease progression ; epigallocatechin gallate ; homeostasis ; prostatic neoplasms ; quercetin ; resveratrol ; transcription factors ; zinc ; zinc finger motif
Language	English
Dates of publication	2021-0530
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13061867
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mitochondrial Sirtuins in Skin and Skin Cancers.

Su, Shengqin / Ndiaye, Mary / Singh, Chandra K / Ahmad, Nihal

Photochemistry and photobiology

2020 Volume 96, Issue 5, Page(s) 973–980

Abstract: Mammalian sirtuins (SIRTs 1-7) are a family of NAD+-dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs -3, -4 and -5 are located in the ... ...

Abstract	Mammalian sirtuins (SIRTs 1-7) are a family of NAD+-dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs -3, -4 and -5 are located in the mitochondria and have been implicated in caloric restriction, oxidative stress, aging and various human diseases. Emerging evidence has found dysregulation of mitochondrial sirtuins in multiple dermatological conditions, including responses to ultraviolet radiation (UVR), suggesting their importance in maintaining skin health. In this review, we discuss the roles and implications of mitochondrial sirtuins in cutaneous cellular processes, and their emerging potential as a target for the management of skin diseases, including skin cancer. Among mitochondrial sirtuins, SIRT3 is the most studied and linked to multiple skin conditions and diseases (keratinocyte differentiation, wound healing, chronological aging, UVR and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). SIRT4 has been connected to keratinocyte differentiation, chronological aging, UVR response, alopecia, BCC and SCC. Further, SIRT5 has been associated with keratinocyte differentiation, melanoma, BCC and SCC. Overall, while there is compelling evidence for the involvement of mitochondrial sirtuins in skin, additional detailed studies are needed to understand their exact roles in skin and skin cancers.
MeSH term(s)	Cell Differentiation/physiology ; Humans ; Keratinocytes/cytology ; Keratinocytes/drug effects ; Keratinocytes/radiation effects ; Mitochondria/metabolism ; Ozone/toxicity ; Sirtuins/metabolism ; Sirtuins/physiology ; Skin/drug effects ; Skin/metabolism ; Skin/radiation effects ; Skin Aging ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Ultraviolet Rays
Chemical Substances	Ozone (66H7ZZK23N) ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2020-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	123540-0
ISSN	1751-1097 ; 0031-8655
ISSN (online)	1751-1097
ISSN	0031-8655
DOI	10.1111/php.13254
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Article: Genetic Manipulation of Sirtuin 3 Causes Alterations of Key Metabolic Regulators in Melanoma.

Singh, Chandra K / George, Jasmine / Chhabra, Gagan / Nihal, Minakshi / Chang, Hao / Ahmad, Nihal

Frontiers in oncology

2021 Volume 11, Page(s) 676077

Abstract: The mitochondrial sirtuin SIRT3 plays key roles in cellular metabolism and energy production, which makes it an obvious target for the management of cancer, including melanoma. Previously, we have demonstrated that SIRT3 was constitutively upregulated in ...

Abstract	The mitochondrial sirtuin SIRT3 plays key roles in cellular metabolism and energy production, which makes it an obvious target for the management of cancer, including melanoma. Previously, we have demonstrated that SIRT3 was constitutively upregulated in human melanoma and its inhibition resulted in anti-proliferative effects
Language	English
Publishing date	2021-04-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.676077
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Article ; Online: Dietary Phytochemicals in Zinc Homeostasis: A Strategy for Prostate Cancer Management.

Singh, Chandra K / Chhabra, Gagan / Patel, Arth / Chang, Hao / Ahmad, Nihal

Nutrients

2021 Volume 13, Issue 6

Abstract	Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer (PCa), Zn levels are significantly decreased and inversely correlated with disease progression. Ideally, restoration of adequate Zn levels in premalignant/malignant prostate cells could abort prostate malignancy. However, studies have shown that Zn supplementation is not an efficient way to significantly increase Zn concentrations in PCa. Based on a limited number of investigations, the reason for the lower levels of Zn in PCa is believed to be the dysregulation of Zn transporters (especially ZIP and ZnT family of proteins), metallothioneins (for storing and releasing Zn), and their regulators (e.g., Zn finger transcription factor RREB1). Interestingly, the level of Zn in cells has been shown to be modulated by naturally occurring dietary phytochemicals. In this review, we discussed the effect of selected phytochemicals (quercetin, resveratrol, epigallocatechin-3-gallate and curcumin) on Zn functioning and proposes that Zn in combination with specific dietary phytochemicals may lead to enhanced Zn bioaccumulation in the prostate, and therefore, may inhibit PCa.
MeSH term(s)	Homeostasis/physiology ; Humans ; Male ; Phytochemicals/metabolism ; Phytochemicals/therapeutic use ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/physiopathology ; Zinc/metabolism
Chemical Substances	Phytochemicals ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2021-05-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13061867
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Article: PLK1 inhibition-based combination therapies for cancer management.

Su, Shengqin / Chhabra, Gagan / Singh, Chandra K / Ndiaye, Mary A / Ahmad, Nihal

Translational oncology

2021 Volume 16, Page(s) 101332

Abstract: Polo-like kinase I (PLK1), a cell cycle regulating kinase, has been shown to have oncogenic function in several cancers. Although PLK1 inhibitors, such as BI2536, BI6727 (volasertib) and NMS-1286937 (onvansertib) are generally well-tolerated with a ... ...

Abstract	Polo-like kinase I (PLK1), a cell cycle regulating kinase, has been shown to have oncogenic function in several cancers. Although PLK1 inhibitors, such as BI2536, BI6727 (volasertib) and NMS-1286937 (onvansertib) are generally well-tolerated with a favorable pharmacokinetic profile, clinical successes are limited due to partial responses in cancer patients, especially those in advanced stages. Recently, combination therapies targeting multiple pathways are being tested for cancer management. In this review, we first discuss structure and function of PLK1, role of PLK1 in cancers, PLK1 specific inhibitors, and advantages of using combination therapy versus monotherapy followed by a critical account on PLK1-based combination therapies in cancer treatments, especially highlighting recent advancements and challenges. PLK1 inhibitors in combination with chemotherapy drugs and targeted small molecules have shown superior effects against cancer both in vitro and in vivo. PLK1-based combination therapies have shown increased apoptosis, disrupted cell cycle, and potential to overcome resistance in cancer cells/tissues over monotherapies. Further, with successes in preclinical experiments, researchers are validating such approaches in clinical trials. Although PLK1-based combination therapies have achieved initial success in clinical studies, there are examples where they have failed to improve patient survival. Therefore, further research is needed to identify and validate novel biologically informed co-targets for PLK1-based combinatorial therapies. Employing a network-based analysis, we identified potential PLK1 co-targets that could be examined further. In addition, understanding the mechanisms of synergism between PLK1 inhibitors and other agents may lead to a better approach on which agents to pair with PLK1 inhibition for optimum cancer treatment.
Language	English
Publishing date	2021-12-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2443840-6
ISSN	1936-5233
ISSN	1936-5233
DOI	10.1016/j.tranon.2021.101332
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Article ; Online: Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment.

Chhabra, Gagan / Singh, Chandra K / Amiri, Deeba / Akula, Neha / Ahmad, Nihal

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 5

Abstract: Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune ...

Abstract	Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol's effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Humans ; Immunomodulation ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Resveratrol/pharmacology ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
Chemical Substances	Antioxidants ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2021-03-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26051343
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