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- Haffo, L, et al.
(författare)
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Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 12671-
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Tidskriftsartikel (refereegranskat)abstract
- The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1Met) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs). We show here that the Michael acceptor methylene quinuclidinone (MQ), the active form of APR-246, is a potent direct inhibitor of Trx1 and Grx1 by reacting with sulfhydryl groups in the enzymes. The inhibition of Trx1 and Grx1 by APR-246/MQ is reversible and the inhibitory efficiency is dependent on the presence of glutathione. APR-246/MQ also inhibits Trxs in mutant p53-expressing Saos-2 His-273 cells, showing modification of Trx1 and mitochondrial Trx2. Inhibition of the Trx and Grx systems leads to insufficient reducing power to deoxyribonucleotide production for DNA replication and repair and peroxiredoxin for removal of ROS. We also demonstrate that APR-246 and MQ inhibit ribonucleotide reductase (RNR) in vitro and in living cells. Our results suggest that APR-246 induces tumor cell death through both reactivations of mutant p53 and inhibition of cellular thiol-dependent redox systems, providing a novel strategy for cancer therapy.
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| 9. |
- Kelly, GL, et al.
(författare)
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Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53
- 2014
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Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 28:1, s. 58-70
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Tidskriftsartikel (refereegranskat)abstract
- The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustain c-MYC-driven lymphoma growth to reveal which should be targeted for cancer therapy. Remarkably, inducible Cre-mediated deletion of even a single Mcl-1 allele substantially impaired the growth of c-MYC-driven mouse lymphomas. Mutations in p53 could diminish but not obviate the dependency of c-MYC-driven mouse lymphomas on MCL-1. Importantly, targeting of MCL-1 killed c-MYC-driven human Burkitt lymphoma cells, even those bearing mutations in p53. Given that loss of one allele of Mcl-1 is well tolerated in healthy tissues, our results suggest that therapeutic targeting of MCL-1 would be an attractive therapeutic strategy for MYC-driven cancers.
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- Sansone, Martina, et al.
(författare)
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Molecular characterization of a nosocomial outbreak of influenza B virus in an acute care hospital setting
- 2019
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Ingår i: Journal of Hospital Infection. - : Elsevier BV. - 0195-6701. ; 101:1, s. 30-37
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To describe a hospital outbreak of influenza B virus (InfB) infection during season 2015/2016 by combining clinical and epidemiological data with molecular methods. Methods: Twenty patients diagnosed with InfB from a hospital outbreak over a four-week-period were included. Nasopharyngeal samples (NPS) positive for InfB by multiplex real-time polymerase chain reaction were sent for lineage typing and whole genome sequencing (WGS). Medical records were reviewed retrospectively for data regarding patient characteristics, localization, exposure and outcome, and assembled into a timeline. In order to find possible connections to the hospital outbreak, all patients with a positive NPS for influenza from the region over an extended time period were also reviewed. Findings: All 20 cases of InfB were of subtype B/Yamagata, and 17 of 20 patients could be linked to each other by either shared room or shared ward. WGS was successful or partially successful for 15 of the 17 viral isolates, and corroborated the epidemiological link supporting a close relationship. In the main affected ward, 19 of 75 inpatients were infected with InfB during the outbreak period, resulting in an attack rate of 25%. One probable case of influenza-related death was identified. Conclusion: InfB may spread within an acute care hospital, and advanced molecular methods may facilitate assessment of the source and extent of the outbreak. A multifaceted approach, including rapid diagnosis, early recognition of outbreak situations, simple rules for patient management and the use of regular infection control measures, may prevent nosocomial transmission of influenza virus. (C) 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
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- Ceder, S, et al.
(författare)
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Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells
- 2021
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:7, s. 709-
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Tidskriftsartikel (refereegranskat)abstract
- Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.
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| 23. |
- Cheteh, EH, et al.
(författare)
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Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death
- 2017
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 8:6, s. e2848-
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Tidskriftsartikel (refereegranskat)abstract
- Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs. Co-culture with prostate CAFs or CAF-conditioned medium attenuated DNA damage and the p53 response to chemotherapeutic drugs and enhanced prostate cancer cell survival. CAF-conditioned medium inhibited the accumulation of doxorubicin, but not taxol, in prostate cancer cells in a manner that was associated with increased cancer cell glutathione levels. A low molecular weight fraction (<3 kDa) of CAF-conditioned medium had the same effect. CAF-conditioned medium also inhibited induction of reactive oxygen species (ROS) in both doxorubicin- and taxol-treated cancer cells. Our findings suggest that CAFs can enhance drug resistance in cancer cells by inhibiting drug accumulation and counteracting drug-induced oxidative stress. This protective mechanism may represent a novel therapeutic target in cancer.
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| 24. |
- Cheteh, EH, et al.
(författare)
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Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells
- 2020
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Ingår i: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 6:1, s. 42-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.
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| 25. |
- Evgenieva, Tsvetina, et al.
(författare)
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Lidar, ceilometer and sun photometer investigation of the aerosol optical characteristics in the troposphere over Sofia, Bulgaria
- 2010
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Ingår i: Comptes Rendus de l'Academie Bulgare des Sciences / Proceedings of the Bulgarian Academy of Sciences. - 1310-1331 .- 2367-5535. ; 63:8, s. 1191-1200
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Tidskriftsartikel (refereegranskat)abstract
- The paper presents the results from planetary boundary layer (PBL) height and aerosol optical depth (AOD) measurements carried out in two different experimental sites in Sofia as well as from three-point measurements of aerosol number concentration.The main aim of the present investigation is to determine optical and microphysical characteristics of the atmospheric aerosol in three points of the valley and their variation during the PBL formation over urban area, park zone and mountain site. Four instruments (lidar, ceilometer, aerosol particle counter and sun photometer) were used in this study.The experimental AOD data obtained at lambda = 500nm gave values in the range from 0.22 to 0.41 in case of cloud-free skies and up to around 0.8 under partly cloudy conditions. Aerosol particle counter data on aerosol-particle concentration variations in the size range 0.3-1 mu m provided supportive information on the evolution of the valley-mountain aerosol in time and height during the mixing layer development. Joint interpretation of sun photometer, aerosol lidar and ceilometer CHM 15k data allow the influence of the main part of the atmospheric aerosol in the planetary boundary layer to be accounted as well as the significant influence of aerosol layers and high clouds on AOD values.
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- Evgenieva, Tsvetina, et al.
(författare)
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Three-point observation in the troposphere over Sofia-Plana Mountain,Bulgaria
- 2011
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Ingår i: International Journal of Remote Sensing. - : Informa UK Limited. - 0143-1161 .- 1366-5901. ; 32:24, s. 9343-9363
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Tidskriftsartikel (refereegranskat)abstract
- Based on a novel combination of approaches and instruments, this article presents campaign-based results from atmospheric boundary layer (ABL) height and aerosol optical depth (AOD) measurements carried out at two different experimental sites in Sofia, as well as from three-point measurements of aerosol number concentrations. Several instruments (lidar (developed by the IE), ceilometer, aerosol particle counter, sun photometer and meteorological sensors) were used in this study. Based on joint interpretation of the instruments' data we assess the influence of the atmospheric aerosol in the planetary boundary layer and the significant influence of aerosol layers and high clouds on AOD values. Measurements of AOD in the city basin gave values in the range 0.22-0.41 for cloud-free skies, and up to around 0.8 under partly cloudy conditions. The information obtained during the two campaigns indicates that aerosol particle concentrations were lower in park areas than along heavy-traffic thoroughfares in the city, but higher than in the mountain area. In conclusion, our study demonstrates the potential of employing a broad array of instruments for the study of boundary layer and aerosol over large, valley-situated and heavily urbanized city areas.
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| 31. |
- Girnita, L., et al.
(författare)
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Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53 : Functional impact
- 2000
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 60:18, s. 5278-5283
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the functional impact of p53 on insulin-like growth factor I receptor (IGF-IR) expression in malignant cells. Using the BL-41tsp53-2 cell line, a transfectant carrying temperature-sensitive (ts) p53 and endogenous mutant p53 (codon 248), we demonstrated a drastic down-regulation of plasma membrane-bound IGF-IRs on induction of wild-type p53, However, a similar response was obtained by treatment of BL-41tsp53-2 cells expressing mutant ts p53 with a p53 antisense oligonucleotide. Thus, even if the negative effect of wild-type p53 predominates under a competitive condition, these data indicate that mutant p53 may be important for up-regulation of IGF-IR, To further elucidate this issue, three melanoma cell lines (BE, SK-MEL-5, and SK-MEL-28) that over expressed p53 were investigated. The BE cell line has a hot spot mutation (codon 248) and expresses only codon 248-mutant p53, SK-MEL-28 has a point mutation at codon 145. SK-MEL-5 cells did not exhibit any p53 mutations, but the absence of p21(Waf1) expression suggested functionally aberrant p53. Our data suggest that interaction with Mdm-2 may underlie p53 inactivation in these cells, Using p53 antisense oligonucleotides, we demonstrated a substantial down-regulation of cell surface expression of IGF-IR proteins in all melanoma cell lines after 24 h, This was paralleled by decreased tyrosine phosphorylation of IGF-IR and growth arrest, and, subsequently, massive cell death was observed (this was also seen in BL-41tsp53-2 cells with mutant conformation of ts p53). Taken together, our results suggest that up-regulation of IGF-IR as a result of expression of aberrant p53 may be important for the growth and survival of malignant cells.
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- Ibrahim, Muhammad Asim, 1980-, et al.
(författare)
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Mitigating the emissions released from spontaneous fires at biomass storages : A footstep towards sustainability
- 2015
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Ingår i: 23rd European Biomass Conference and Exhibition, Vienna, Austria, 1-4 June 2015. - 9788889407516 ; , s. 1550-1557
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Konferensbidrag (refereegranskat)abstract
- Fires at the material storages sites of manucipal and industrial sectors are a major environmental risk and have increased significantly. Toxic emissions released from such open fires have severe environmental and health consequences. Considering that it is not possible to install any unit operation to control the emissions released from such open fires, the possibilities to employ natural vegetation to act as a sink for aerosol particles released from open fires was investigated. A series of tests was conducted in a controlled wind tunnel environment. Smoke was generated in a smoke-aerosol generator and measurements of smoke concentrations upwind and downwind of “green filter packs” (vegetation filters) were made. Measurements involved laser-based particle counters, two-stage Nuclepore filter systems, and Solid Phase Microextraction (SPME) techniques followed by Gas Chromatography-Mass Spectrometry (GC-MS). The main objective of the work was to illustrate ways to design experiments that can assist in the study of vegetation as “pollution screens”. Our observations and findings imply that several refinements to the experimental design will be needed, including with respect to methods for assessing the distribution of particle number and mass as a function of particle size.
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- Liu, DS, et al.
(författare)
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Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 14844-
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Tidskriftsartikel (refereegranskat)abstract
- TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC− inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.
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| 44. |
- Lövbrand, Eva, et al.
(författare)
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Earth System governmentality Reflections on science in the Anthropocene
- 2009
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Ingår i: GLOBAL ENVIRONMENTAL CHANGE-HUMAN AND POLICY DIMENSIONS. - : Elsevier BV. - 0959-3780 .- 1872-9495. ; 19:1, s. 7-13
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Tidskriftsartikel (refereegranskat)abstract
- This paper examines Earth System Science as a novel approach to global environmental change research. Drawing upon Michel Foucaults governmentality concept, the paper opens up the Earth System metaphor to political analysis and asks what it does to our understanding of nature and society as a governable domain. We trace the scientific practices that have produced the Earth System as a thinkable analytical category back to the International Geophysical Year in 1957. We also identify the Anthropocene as a central and yet ambiguous system of thought for Earth System Science that harbours different strategies for sustainability in terms of (1) the persons over whom government is to be exercised; (2) the distribution of tasks and actions between authorities; and (3) contrasting ideals or principles for how government should be directed.
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