| 1. |
- Kolosenko, Iryna, et al.
(författare)
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Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:4, s. E51-E61
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors. What's new? Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.
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| 2. |
- Licciardello, Riccardo, et al.
(författare)
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Integrating yards, network and optimisation models towards real-time rail freight yard operations
- 2020
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Ingår i: Ingegneria Ferroviaria. - Rome, Italy : Collegio Ingegneri Ferroviari Italiani. - 0020-0956. ; 6, s. 417-440
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the state of advancement achieved in the OptiYard research project in the use of optimisation algorithms in interaction with microsimulation of the rail-yard and surrounding network towards realtime yard management and communication with the network. Two case studies, a hump marshalling yard (mainly Single Wagon Load traffic) and a flat shunting yard (mainly intermodal traffic), were represented with state-of-the art microsimulation models, combined with innovative optimisation algorithms. Some specialistic information on the nature of the models is provided. However, the focus is oriented to railway engineers, with a description of the interactions between the models in producing outputs that are useful both to the yard dispatcher (decisions on staff, track, locomotive assignment, order of operations) and the infrastructure manager of the surrounding network (expected times of departure, availability of tracks in the yard).
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| 3. |
- Mancina, Rosellina Margherita, et al.
(författare)
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PSD3 downregulation confers protection against fatty liver disease.
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:1, s. 60-75
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
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| 4. |
- Mazurkiewicz, Magdalena, et al.
(författare)
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Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:13, s. 21115-21127
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Tidskriftsartikel (refereegranskat)abstract
- The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability. VLX1570 treatment increased the levels of a number of proteins, including the chaperone HSP70B , the oxidative stress marker heme oxygenase-1 (HO-1) and the cell cycle regulator p21(Cip1). Unexpectedly, polybiquitin accumulation was found to be uncoupled from ER stress in ALL cells. Thus, increased phosphorylation of eIF2a occurred only at supra-pharmacological VLX1570 concentrations and did not correlate with polybiquitin accumulation. Total cellular protein synthesis was found to decrease in the absence of eIF2a phosphorylation. Furthermore, ISRIB (Integrated Stress Response inhibitor) did not overcome the inhibition of protein synthesis. We finally show that VLX1570 can be combined with L-asparaginase for additive or synergistic antiproliferative effects on ALL cells. We conclude that ALL cells are highly sensitive to the proteasome DUB inhibitor VLX1570 suggesting a novel therapeutic option for this disease.
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| 5. |
- Minbashi, Niloofar, 1990-
(författare)
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Application of Predictive Analytics for Shunting Yard Delays
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Increasing the modal share of rail freight transport is one of the main ways to achieve carbon neutrality in Europe. The perceived low reliability and predictability of rail freight services is one of the main challenges to overcome in reaching this target. Shunting yards play an important role in providing more reliable and predictable freight trains. Shunting yard departure deviations impact other trains on mixed-traffic railway networks. Predictable departures from shunting yards increase the overall predictability of freight train runs along the network.The primary focus of this thesis is on how to apply data-driven approaches to increase the predictability of shunting yard departures. Descriptive analytics were used to provide enhanced insight into shunting yard departures, and predictive analytics were applied to develop shunting yard departure deviation prediction models. Finally, hybrid modeling was used to integrate the yard departure prediction model with other simulation models for wider application. The results from this thesis contribute to providing a deeper understanding of shunting yard departure deviations, interactions between shunting yards and the network through departure and arrival deviations, and how to model these deviations by applying data-driven approaches. These results from five published research papers are included and presented in this doctoral thesis.Descriptive analytics methods are applied in papers I and II to explore the probability distribution of departure deviations and the impact of the network on departure delays. The results show that positive and negative departure deviations have different distributions for different shunting yards. Moreover, network usage fluctuations over shorter timespans impact departure delays, whereas no correlation is established between network impact, defined as congestion in the arrival yard, and departure delays.Predictive analytics is applied in paper III by developing tree-based algorithms to classify the status of shunting yard departures. The departure status are imbalanced; the majority are early, and the minority are delayed. The results show that applying methods to overcome imbalanced data sets can improve the prediction of delayed departures.The models developed in paper III are extended in papers IV and V to predict departure deviations in a combined modeling approach for two separate applications. In paper IV, a machine learning-assisted macro simulation model framework is introduced to integrate yard departure predictions into a macro simulation network model and predict the arrivals to the next yard. The results show improved prediction accuracy compared to a basic machine learning model and a baseline timetable model.Finally, in paper V, the generalization of the yard departure prediction model is explored by applying a simulation-assisted machine learning modeling approach where the model is trained on real-world European yard data and North American simulation yard data. The results show the model has a notable generalized performance with both data types.
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| 6. |
- Mofers, Arjan, et al.
(författare)
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Proteasome-associated deubiquitinases and cancer
- 2017
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Ingår i: Cancer Metastasis Review. - : SPRINGER. - 0167-7659 .- 1573-7233. ; 36:4, s. 635-653
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Forskningsöversikt (refereegranskat)abstract
- Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
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| 7. |
- Pellegrini, Barbara, et al.
(författare)
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Biomechanical and energetic determinants of technique selection in classical cross-country skiing
- 2013
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Ingår i: Human Movement Science. - : Elsevier. - 0167-9457 .- 1872-7646. ; 32:6, s. 1415-1429
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Tidskriftsartikel (refereegranskat)abstract
- Classical cross-country skiing can be performed using three main techniques: diagonal stride (DS), double poling (DP), and double poling with kick (DK). Similar to other forms of human and animal gait, it is currently unclear whether technique selection occurs to minimize metabolic cost or to keep some mechanical factors below a given threshold. The aim of this study was to find the determinants of technique selection. Ten male athletes roller skied on a treadmill at different slopes (from 0° to 7° at 10km/h) and speeds (from 6 to 18km/h at 2°). The technique preferred by skiers was gathered for every proposed condition. Biomechanical parameters and metabolic cost were then measured for each condition and technique. Skiers preferred DP for skiing on the flat and they transitioned to DK and then to DS with increasing slope steepness, when increasing speed all skiers preferred DP. Data suggested that selections mainly occur to remain below a threshold of poling force. Second, critically low values of leg thrust time may limit the use of leg-based techniques at high speeds. A small role has been identified for the metabolic cost of locomotion, which determined the selection of DP for flat skiing.
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| 8. |
- Pellegrini, Paola, et al.
(författare)
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A drug screening assay on cancer cells chronically adapted to acidosis
- 2018
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.
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| 9. |
- Pellegrini, Paola, 1986-, et al.
(författare)
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Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:13
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib.
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| 10. |
- Pellegrini, Paola, et al.
(författare)
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Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:24, s. 35703-35723
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Tidskriftsartikel (refereegranskat)abstract
- Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC-like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits.
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