| 11. |
- Hillert, Ellin-Kristina, et al.
(author)
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Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation
- 2019
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In: Cancer Letters. - : ELSEVIER IRELAND LTD. - 0304-3835 .- 1872-7980. ; 448, s. 70-83
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Journal article (peer-reviewed)abstract
- Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation. b-AP15 was found to affect organelle transport in treated cells, raising the possibility that microtubule-transport of toxic protein aggregates is inhibited, leading to enhanced cytotoxicity. In contrast to the antiproliferative effects of the clinically used proteasome inhibitor bortezomib, the effects of b-AP15 are not further enhanced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Our results suggest an inhibitory effect of b-AP15 on the transport of misfolded proteins, resulting in a lack of aggresome formation, and a strong proteotoxic stress response.
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| 12. |
- Li, Ze, et al.
(author)
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Asymmetric Modulated Predictive Current Control for Dual Three-Phase PMSM With Improved Performance
- 2024
-
In: 2024 IEEE 10th International Power Electronics and Motion Control Conference, IPEMC 2024 ECCE Asia. - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. 4795-4800
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Conference paper (peer-reviewed)abstract
- Dual three-phase PMSM (DTP-PMSM) has gained significant attention benefiting from their exceptional reliability and high torque density. However, DTP-PMSM exhibits poor steady-state performance and large calculation amount with the conventional finite-control-set predictive current control. To address these concerns, an asymmetric modulated predictive current control (AM-PCC) for DTP-PMSM is presented. Therein, the three-phase decomposition and deadbeat control scheme are combined to eliminate the weighting factor and optimize the execution efficiency. An asymmetric modulation strategy is presented and integrated into PCC to reduce the current harmonics and switching frequency. Extensive simulation tests are conducted to demonstrate the effectiveness of the proposed AM-PCC scheme.
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| 13. |
- Li, Ze, et al.
(author)
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Modulated-Virtual-Vector-Based Predictive Current Control for Dual Three-Phase PMSM With Enhanced Steady-State Performance
- 2023
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In: IECON 2023 - 49th Annual Conference of the IEEE Industrial Electronics Society. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- Dual three-phase permanent magnet synchronous machine (DTP-PMSM) has attracted great attention due to its high reliability and high-power output capacities. However, the conventional single-voltage-vector-based predictive current control (SV-PCC) for DTP-PMSM presents high torque ripple and current harmonics, and high computational burden. To solve those issues, a modulated-virtual-vector-based PCC (MVV-PCC) for DTP-PMSM is proposed in this paper. Wherein, twenty-four VVs are synthesized by the inherent voltage vectors, and two VVs and one zero voltage vector with optimal duty cycles are determined and applied in each sampling period to improve the steady-state performance. The selection of optimal VVs and the calculation of the optimal duty cycles are simplified by integrating the deadbeat control and modulation scheme. Various comparisons are carried out to validate the effectiveness and superiority of the proposed MVV-PCC strategy.
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| 14. |
- Li, Ze, et al.
(author)
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Multi-Virtual-Vector-Based Predictive Current Control for Fault-Tolerant Inverter-Fed Dual Three-Phase Permanent Magnet Synchronous Machines
- 2023
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In: 2023 IEEE International Conference on Predictive Control of Electrical Drives and Power Electronics, PRECEDE 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- Dual three-phase permanent magnet synchronous machine (DTP-PMSM) has received extensive interests due to its inherent fault-tolerant capability. However, conventional single-virtual-vector-based predictive current control (SVV-PCC) for DTP-PMSM with open-phase fault (OPF) presents poor steady-state performance and high computational burden. To address these issues, a multi-virtual-vector-based PCC (MVV-PCC) for DTP-PMSM with OPF is proposed in this paper. Therein, two virtual vectors and one zero vector with optimal duty cycles are determined in each sampling period to improve the steady-state performance. A simplification strategy for selecting the optimal virtual vectors and calculating the optimal duty cycles is established to reduce the computational burden in digital implementation. Extensive comparisons are conducted to verify the effectiveness of the proposed MVV-PCC scheme.
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| 15. |
- Lindell, Emma, et al.
(author)
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Exploring the Enigma : The Role of the Epithelial Protein Lost in Neoplasm in Normal Physiology and Cancer Pathogenesis
- 2024
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:9
-
Research review (peer-reviewed)abstract
- The cytoskeleton plays a pivotal role in maintaining the epithelial phenotype and is vital to several hallmark processes of cancer. Over the past decades, researchers have identified the epithelial protein lost in neoplasm (EPLIN, also known as LIMA1) as a key regulator of cytoskeletal dynamics, cytoskeletal organization, motility, as well as cell growth and metabolism. Dysregulation of EPLIN is implicated in various aspects of cancer progression, such as tumor growth, invasion, metastasis, and therapeutic resistance. Its altered expression levels or activity can disrupt cytoskeletal dynamics, leading to aberrant cell motility and invasiveness characteristic of malignant cells. Moreover, the involvement of EPLIN in cell growth and metabolism underscores its significance in orchestrating key processes essential for cancer cell survival and proliferation. This review provides a comprehensive exploration of the intricate roles of EPLIN across diverse cellular processes in both normal physiology and cancer pathogenesis. Additionally, this review discusses the possibility of EPLIN as a potential target for anticancer therapy in future studies.
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| 16. |
- Lindell, Emma, et al.
(author)
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Quiescent Cancer Cells : A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse
- 2023
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:4
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Research review (peer-reviewed)abstract
- Quiescent cancer cells (QCCs) are nonproliferating cells arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, and some treatments could further lead to a higher proportion of QCCs in tumors. QCCs are also associated with cancer recurrence since they can re-enter a proliferative state when conditions are favorable. As QCCs lead to drug resistance and tumor recurrence, there is a great need to understand the characteristics of QCCs, decipher the mechanisms that regulate the proliferative–quiescent transition in cancer cells, and develop new strategies to eliminate QCCs residing in solid tumors. In this review, we discussed the mechanisms of QCC-induced drug resistance and tumor recurrence. We also discussed therapeutic strategies to overcome resistance and relapse by targeting QCCs, including (i) identifying reactive quiescent cancer cells and removing them via cell-cycle-dependent anticancer reagents; (ii) modulating the quiescence-to-proliferation switch; and (iii) eliminating QCCs by targeting their unique features. It is believed that the simultaneous co-targeting of proliferating and quiescent cancer cells may ultimately lead to the development of more effective therapeutic strategies for the treatment of solid tumors.
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| 17. |
- Lu, Xi, et al.
(author)
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Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells
- 2023
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In: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 14:10
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
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| 18. |
- Ma, Ran, et al.
(author)
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Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells.
- 2017
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 109:3, s. 1-14
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Journal article (peer-reviewed)abstract
- Background: Breast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer.Methods: We characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ERβ-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n = 4 or 5 per group) were used to study the role of ERs during tumorigenesis.Results: We identified an absence of ERα but upregulation of ERβ in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ERβ caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ERβ-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ERβ (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts.Conclusion: We identify ERβ as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.
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| 19. |
- Mao, Yumeng, et al.
(author)
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IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
- 2016
-
In: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 128:11, s. 1475-1489
-
Journal article (peer-reviewed)abstract
- Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
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| 20. |
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