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- Ferreira, Mjv, et al.
(författare)
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Poster Session 3 : Tuesday 5 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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- Eshtad, S, et al.
(författare)
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hMYH and hMTH1 cooperate for survival in mismatch repair defective T-cell acute lymphoblastic leukemia
- 2016
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Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 5:12, s. e275-
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Tidskriftsartikel (refereegranskat)abstract
- hMTH1 is an 8-oxodGTPase that prevents mis-incorporation of free oxidized nucleotides into genomic DNA. Base excision and mismatch repair pathways also restrict the accumulation of oxidized lesions in DNA by removing the mis-inserted 8-oxo-7,8-dihydro-2'-deoxyguanosines (8-oxodGs). In this study, we aimed to investigate the interplay between hMYH DNA glycosylase and hMTH1 for cancer cell survival by using mismatch repair defective T-cell acute lymphoblastic leukemia (T-ALL) cells. To this end, MYH and MTH1 were silenced individually or simultaneously using small hairpin RNAs. Increased sub-G1 population and apoptotic cells were observed upon concurrent depletion of both enzymes. Elevated cell death was consistent with cleaved caspase 3 accumulation in double knockdown cells. Importantly, overexpression of the nuclear isoform of hMYH could remove the G1 arrest and partially rescue the toxicity observed in hMTH1-depleted cells. In addition, expression profiles of human DNA glycosylases were generated using quantitative reverse transcriptase–PCR in MTH1 and/or MYH knockdown cells. NEIL1 DNA glycosylase, involved in repair of oxidized nucleosides, was found to be significantly downregulated as a cellular response to MTH1–MYH co-suppression. Overall, the results suggest that hMYH and hMTH1 functionally cooperate for effective repair and survival in mismatch repair defective T-ALL Jurkat A3 cells.
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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Mahmood, Sultan, et al.
(författare)
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RECOMBINATION RATE COEFFICIENTS OF BORON-LIKE Ne
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 771:2, s. 78-
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Tidskriftsartikel (refereegranskat)abstract
- Recombination of Ne5+ was measured in a merged-beam type experiment at the heavy-ion storage ring CRYRING. In the collision energy range 0-110 eV resonances due to 2s(2)2p -> 2s2p(2) (Delta n=0) and 2s(2)2p -> 2s(2)3l (Delta n=1), core excitations were observed. The experimentally derived rate coefficients agree well with the calculations obtained using AUTOSTRUCTURE. At low energies, recombination is dominated by resonances belonging to the spin-forbidden 2s2p(2)(P-4(J))nl series. The energy-dependent rate coefficients were convoluted with a Maxwell-Boltzmann electron energy distribution to obtain plasma recombination rate coefficients. The data from the literature deviate from the measured results at low temperature.
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- Orban, Istvan, 1980-, et al.
(författare)
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Determination of the recombination rate coefficients for Na-like Si IV forming Mg-like Si III
- 2006
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 459:1, s. 291-296
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Tidskriftsartikel (refereegranskat)abstract
- Aims. Absolute, total recombination rate coefficients for Si IV were determined using the CRYRING heavy-ion storage ring. Calculated rate coefficients were used to estimate recombination into states that could not be detected in the experiment because of field ionization. Total, as well as separate, radiative and dielectronic plasma recombination rate coefficients were determined. Methods. Stored ions were merged with an expanded electron beam in the electron cooler section of the storage ring. Recombined ions were separated from the stored ion beam in the first dipole magnet after the electron cooler and were detected with unity efficiency. The absolute radiative and dielectronic recombination rate coefficients were obtained over a center-of-mass energy range of 0-20 eV, covering Δ n = 0 core excitations up to the 3s → 3d series limit. The results of an intermediate coupling AUTOSTRUCTURE calculation were compared with the experiment. The theoretical results were also used to estimate the contribution to dielectronic recombination by high Rydberg states, which were not detected because of field ionization. The spectra were convoluted with Maxwell-Boltzmann energy distributions in the 103-10 6 K temperature range. Results. The resulting plasma recombination rate coefficients are presented and compared with theoretical results frequently used for plasma modeling. In the 103-104 K range, a significant underestimation of the calculated dielectronic recombination plasma rate coefficients was observed. Above 3 × 104 K, the agreement between our dielectronic recombination plasma rate coefficients and two of the previously published rate coefficients is better than 20%. Conclusions. The observed differences between the experimental and calculated recombination rate coefficients at low temperatures reflect the need for benchmarking experiments. Our experimentally-derived rate coefficients can guide the development of better theoretical models and lead to more accurately-calculated rate coefficients.
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