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- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 4. |
- Gustafsson, Erik, et al.
(författare)
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Carbon cycling on the East Siberian Arctic Shelf – a change in air-sea CO2 flux induced by mineralization of terrestrial organic carbon
- 2017
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189.
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Tidskriftsartikel (refereegranskat)abstract
- Measurements from the SWERUS-C3 and ISSS-08 Arctic expeditions were used to calibrate and validate a new physical-biogeochemical model developed to quantify key carbon cycling processes on the East Siberian Arctic Shelf (ESAS). The model was used in a series of experimental simulations with the specific aim to investigate the pathways of terrestrial dissolved and particulate organic carbon (DOCter and POCter) supplied to the shelf. Rivers supply on average 8.5 Tg C yr−1 dissolved inorganic carbon (DIC), and further 8.5 and 1.1 Tg C yr−1 DOCter and POCter respectively. Based on observed and simulated DOC concentrations and stable isotope values (δ13CDOC) in shelf waters, we estimate that only some 20 % of the riverine DOCter is labile. According to our model results, an additional supply of approximately 14 Tg C yr−1 eroded labile POCter is however required to describe the observed stable isotope values of DIC (δ13CDIC). Degradation of riverine DOCter and POCter results in a 1.8 Tg C yr−1 reduction in the uptake of atmospheric CO2, while degradation of eroded POCter results in an additional 10 Tg C yr−1 reduction. Our calculations indicate nevertheless that the ESAS is an overall small net sink for atmospheric CO2 (1.7 Tg C yr−1). The external carbon sources are largely compensated by a net export from the shelf to the Arctic Ocean (31 Tg C yr−1), and to a smaller degree by a permanent burial in the sediments (2.7 Tg C yr−1).
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- Gustafsson, Robert, et al.
(författare)
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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:4, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.
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- Humborg, Christoph, et al.
(författare)
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Sea-air exchange patterns along the central and outer East Siberian Arctic Shelf as inferred from continuous CO2, stable isotope, and bulk chemistry measurements
- 2017
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 31:7
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Tidskriftsartikel (refereegranskat)abstract
- This large-scale quasi-synoptic study gives a comprehensive picture of sea-air CO 2 fluxes during the melt season in the central and outer Laptev Sea (LS) and East Siberian Sea (ESS). During a 7 week cruise we compiled a continuous record of both surface water and air CO 2 concentrations, in total 76,892 measurements. Overall, the central and outer parts of the ESAS constituted a sink for CO 2 , and we estimate a median uptake of 9.4 g C m -2 yr -1 or 6.6 Tg C yr -1 . Our results suggest that while the ESS and shelf break waters adjacent to the LS and ESS are net autotrophic systems, the LS is a net heterotrophic system. CO 2 sea-air fluxes for the LS were 4.7 g C m -2 yr -1 , and for the ESS we estimate an uptake of 7.2 g C m -2 yr -1 . Isotopic composition of dissolved inorganic carbon (δ 13 C DIC and δ 13 C CO2 ) in the water column indicates that the LS is depleted in δ 13 C DIC compared to the Arctic Ocean (ArcO) and ESS with an offset of 0.5‰ which can be explained by mixing of δ 13 C DIC -depleted riverine waters and 4.0 Tg yr -1 respiration of OC ter ; only a minor part (0.72 Tg yr -1 ) of this respired OC ter is exchanged with the atmosphere. Property-mixing diagrams of total organic carbon and isotope ratio (δ 13 C SPE-DOC ) versus dissolved organic carbon (DOC) concentration diagram indicate conservative and nonconservative mixing in the LS and ESS, respectively. We suggest land-derived particulate organic carbon from coastal erosion as an additional significant source for the depleted δ 13 C DIC .
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- Malm, Joakim, et al.
(författare)
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Using Supplemental Instruction to Bridge the Transition from Secondary to Tertiary Education
- 2012
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Ingår i: International Journal of Education. - : Macrothink Institute, Inc.. - 1948-5476. ; 4:3, s. 13-29
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Tidskriftsartikel (refereegranskat)abstract
- Supplemental Instruction (SI) is today a well known academic assistance program, providing help for students in “difficult” courses at colleges and universities. Little attention has been paid however to the possibility of also implementing the SI program in upper secondary school. In this study we present qualitative results from such an SI program in a Swedish setting. Here, students from the faculty of engineering at Lund University, act as SI leaders at eleven upper secondary schools in the local region, in subjects such as math, physics and chemistry. The main conclusion is that the SI methodology also seems to work in an upper secondary school environment. The students who attend SI regularly appear to obtain new study strategies to increase their understanding of the subject, besides improving on general skills such as teamwork, communicating on a subject, and making presentations in front of others. There are several advantages for the schools and university involved. For example they gain a formal and an informal link, which can prove useful in many circumstances when an exchange of information is needed, and both can use SI as a means to boost recruitment. For the upper secondary school, the students can get an alternative view on subjects, which hopefully stimulates interest and understanding. The students also get a more mature role model to turn to. For the university an additional advantage is that a more informal view of what it is like to study at university can be provided to upper secondary school students.
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- Schüle, Jana, et al.
(författare)
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Down-regulation of the CD3-ζ chain in sentinel node biopsies from breast cancer patients
- 2002
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Ingår i: Breast Cancer Research and Treatment. - 0167-6806 .- 1573-7217. ; 74:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- Background. In several neoplastic diseases, immunosuppression has been shown to correlate with disease stage, progression, and outcome. As the prognosis for metastatic breast cancer is still pessimistic, additional strategies are being sought to improve survival. Local immunosuppression in sentinel node biopsies from 24 evaluable breast cancer patients was studied as a possible way of selecting patients for immunotherapy.Method. Sentinel node biopsy was performed in 24 out of 25 women operated on for primary breast cancer (one was not evaluable). Specimens were snap-frozen and double-stained for the zeta-chain of the T-cell receptor. The degree of down-regulation of the zeta-chain was evaluated in three different lymph-node areas: primary follicles, secondary follicles, and paracortex.Results. Down-regulation of varying degrees was noted in all 24 sentinel node biopsies. A high degree of down-regulation (more than 50% of T-cells not expressing zeta-chain) was seen in the primary follicles in six patients (25%), in the secondary follicles in 13 patients (72%), and in the paracortex in 19 patients (79%).Conclusion. Local down-regulation of an immune function parameter was seen in sentinel node biopsies from breast cancer patients. In addition to possible prognostic implications, the sentinel node might be an appropriate location for detecting early-stage immunological down-regulation, which might open a possibility of selecting patients who could benefit from immunotherapy.
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| 10. |
- Schüle, Jana M, et al.
(författare)
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CD28 expression in sentinel node biopsies from breast cancer patients in comparison with CD3-ζ chain expression
- 2004
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876 .- 1479-5876. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunosuppression is documented in several malignant diseases, including breast cancer. Subsequently, future therapeutic concepts might include immunological approaches. However, detailed knowledge about tumor immunogenicity and host immunoreactivity, and how to assess these adequately, is still limited. We studied CD28 and CD3-ζ expression in sentinel node biopsies (SNB) from breast cancer patients to analyze tumor-related changes in T cell activity. Method: 25 women underwent surgery for primary breast cancer, including SNB. Frozen sections from 21 sentinel nodes could be analyzed with a double-staining technique. CD28 expression was studied in CD4+ and CD8+ T-lymphocyte subsets and compared with CD3-ζ expression in three specified nodal regions. Results: The degree of CD28 expression varied between the different lymph node areas. The lowest degree of CD28 expression was observed in CD4+ T-lymphocytes in the paracortex and germinal centers. Here, a good agreement with CD3-ζ expression was found. A higher CD28 expression was noted in CD4+ T-cells in the primary follicles, where concordance with CD3-ζ expression was weaker. The CD8+ T-lymphocyte subset displayed generally a higher degree of CD28 expression than the CD4+ subset. Conclusion: Sentinel lymph nodes from breast cancer patients displayed local immunosuppression of varying extent. In the areas with the lowest degree of CD28 expression an accordingly low CD3-ζ expression was found. The SNB might prove an important diagnostic tool for the evaluation of interactions between tumor and the host immune system, helping to select patients who might benefit from adjuvant immunotherapy.
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