| 1. |
- 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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| 2. |
- 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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| 3. |
- Mohammed, Mubasher, Msc, et al.
(författare)
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Single-cell transcriptomics reveals transcriptional programs underlying male and female cell fate during Plasmodium falciparum gametocytogenesis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Apicomplexa constitute a large phylum of parasitic protozoa with complex life cycles that typically include meiotic sex. The life cycle of the malaria parasite, Plasmodium falciparum, includes obligate transition and stage development between a human and mosquito host. Asexual parasite replication in the human erythrocytes is followed by differentiation which leads to the formation of a precursor gamete stage, referred to as gametocytes. The gametocyte stage is solely responsible for malaria transmission into the mosquito vector where gamete fusion followed by meiosis occurs. How the parasite differentiates into male and female gametocytes in the absence of sex chromosomes largely remains an open question. Here we combine FACS-based cell enrichment of a gametocyte reporter line followed by single-cell RNA-seq, to enable targeted characterization of the entire gametocyte developmental stage. Our data defines differential transcriptional programs during male and female gametocyte development and highlights a bifurcation point for sexual cell fate. We perform prediction analyses of novel candidate driver genes underlying P. falciparum male and female lineage development. Our data indicate that a large panel of genes linked to the inner membrane complex, known to be involved in morphological life cycle changes, appears to be uniquely expressed in the female gametocyte lineage. Additionally, we delineate the timing of expression of members of the ApiAP2 family of transcription factors and predict their specificity in male and female P. falciparum gametocyte development. A motif-driven gene regulatory network analysis indicates a major role for AP2-G5 in downstream gene regulation along the male lineage developmental trajectory. In total, we anticipate that this study provides the malaria community with an important resource for the development of transmission-blocking intervention strategies.
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| 4. |
- Tlusty, Micheal, et al.
(författare)
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Commentary : Comparing efficiency in aquatic and terrestrial animal production systems
- 2018
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Ingår i: Environmental Research Letters. - : Institute of Physics Publishing. - 1748-9326. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Aquaculture is receiving increased attention from a variety of stakeholders. This is largely due to its current role in the global food system of supplying more than half of the seafood consumed, and also because the industry continues to steadily expand (UN Food and Agriculture Organization 2018). A recent article in Environmental Research Letters, 'Feed conversion efficiency in aquaculture: Do we measure it correctly?', by Fry et al (2018a) found that measuring feed conversion efficiency of selected aquatic and terrestrial farmed animals using protein and calorie retention resulted in species comparisons (least to most efficient) and overlap among species dissimilar from comparisons based on widely used weight-based feed conversion ratio (FCR) values. The study prompted spirited discussions among researchers, industry representatives, and others. A group assembled to write a standard rebuttal, but during this process, decided it was best to engage the study's original authors to join the discourse. Through this collaboration, we provide the resultant additional context relevant to the study in order to advance conversations and research on the use of efficiency measures in aquatic and terrestrial animal production systems.
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| 5. |
- Tlusty, Michael, et al.
(författare)
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Reframing the sustainable seafood narrative
- 2019
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Ingår i: Global Environmental Change. - : Elsevier Ltd. - 0959-3780 .- 1872-9495. ; 59
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Tidskriftsartikel (refereegranskat)abstract
- The dominant sustainable seafood narrative is one where developed world markets catalyze practice improvements by fisheries and aquaculture producers that enhance ocean health. The narrow framing of seafood sustainability in terms of aquaculture or fisheries management and ocean health has contributed to the omission of these important food production systems from the discussion on global food system sustainability. This omission is problematic. Seafood makes critical contributions to food and nutrition security, particularly in low income countries, and is often a more sustainable and nutrient rich source of animal sourced-food than terrestrial meat production. We argue that to maximize the positive contributions that seafood can make to sustainable food systems, the conventional narratives that prioritize seafood's role in promoting ‘ocean health’ need to be reframed and cover a broader set of environmental and social dimensions of sustainability. The focus of the narrative also needs to move from a producer-centric to a ‘whole chain’ perspective that includes greater inclusion of the later stages with a focus on food waste, by-product utilization and consumption. Moreover, seafood should not be treated as a single aggregated item in sustainability assessments. Rather, it should be recognized as a highly diverse set of foods, with variable environmental impacts, edible yield rates and nutritional profiles. Clarifying discussions around seafood will help to deepen the integration of fisheries and aquaculture into the global agenda on sustainable food production, trade and consumption, and assist governments, private sector actors, NGOs and academics alike in identifying where improvements can be made.
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