| 1. |
- Gad, Helge, et al.
(author)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Journal article (peer-reviewed)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.
|
|
| 2. |
- Ecke, Frauke, et al.
(author)
-
Spatio-temporal variation of metals and organic contaminants in bank voles (Myodes glareolus)
- 2020
-
In: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 713
-
Journal article (peer-reviewed)abstract
- Environmental contamination with metals and organic compounds is of increasing concern for ecosystem and human health. Still, our knowledge about spatial distribution, temporal changes and ecotoxicological fate of metals and organic contaminants in wildlife is limited. We studied concentrations of 69 elements and 50 organic compounds in 300 bank voles (Myodes glareolus), Europe's most common mammal, sampled in spring and autumn 2017–2018 in five monitoring areas, representing three biogeographic regions. In addition, we compared measured concentrations with previous results from bank voles sampled within the same areas in 1995–1997 and 2001. In general, our results show regional differences, but no consistent patterns among contaminants and study areas. The exception was for the lowest concentrations of organic contaminants (e.g. perfluorooctane sulfonate, PFOS), which were generally found in the northern Swedish mountain area. Concentrations of metals and organic contaminants in adults varied seasonally with most organic contaminants being higher in spring; likely induced by diet shifts but potentially also related to age differences. In addition, metal concentrations varied between organs (liver vs. kidney), age classes (juveniles vs. adults; generally higher in adults) as well as between males and females. Concentrations of chromium and nickel in kidney and liver in the northernmost mountain area were lower in 2017–2018 than in 1995–1997 and in three of four areas, lead concentrations were lower in 2017–2018 than in 2001. Current metal concentrations (except mercury) are not expected to negatively affect the voles. Concentrations of hexachlorobenzene displayed highest concentrations in 2001 in the mountains, while it was close to detection limit in 2017–2018. Likewise, PFOS concentrations decreased in the mountains and in south-central lowland forests between 2001 and 2017–2018. Our results suggest that season, age class and sex need to be considered when designing and interpreting results from monitoring programs targeting inorganic and organic contaminants in wildlife.
|
|
| 3. |
- Einarsdottir, Berglind Osk, 1979, et al.
(author)
-
A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
-
In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
-
Journal article (peer-reviewed)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
|
|
| 4. |
- Lidman, Johan, et al.
(author)
-
Availability of specific prey types impact pied flycatcher (Ficedula hypoleuca) nestling health in a moderately lead contaminated environment in northern Sweden
- 2020
-
In: Environmental Pollution. - : Elsevier. - 0269-7491 .- 1873-6424. ; 257
-
Journal article (peer-reviewed)abstract
- Anthropogenic metal contamination can cause increased stress in exposed organisms, but it can be difficult to disentangle the anthropogenic influence from natural variation in environmental conditions. In the proximity of a closed lead (Pb)/zinc (Zn) mine in northern Sweden, the health effects of Pb exposure, essential element (calcium [Ca] and Zn) uptake, and prey availability and composition were estimated on pied flycatcher (Ficedula hypoleuca) nestlings, using hemoglobin (Hb) level as a proxy for health. Pb concentration in nestling blood range between 0.00034 and 2.21 mu g/g (ww) and nestlings close to the mine had higher Pb concentrations and lower Hb, but contrary to our hypothesis, Hb was not directly related to Pb accumulation. Proportions of flying terrestrial and aquatic insects in available prey and availability of flying terrestrial insects were positively associated with nestling Hb, whereas the proportion of terrestrial ground living prey, the most common prey type, showed a negative association. This suggests that positive influence of certain prey, which does not have to be the most common in the surroundings, can counteract the negative effects from Pb contamination on bird health. Nestlings inhabiting sites adjacent to lakes had an advantage in terms of prey composition and availability of preferred prey, which resulted in higher Hb. As such, our results show that during moderate exposure to metals, variation in natural conditions, such as prey availability, can have great impact on organism health compared to Pb exposure.
|
|
| 5. |
- Lidman, Johan, et al.
(author)
-
Delayed metamorphosis and increased metal flux from chironomids exposed to contaminated sediment
-
Other publication (other academic/artistic)abstract
- Aquatic insects have been regarded as insensitive to metal contamination, but those assessments have been based on short-term toxicity tests disregarding sensitive life-stages, such as metamorphosis. A hampered metamorphosis may also affect terrestrial ecosystems, via reduced insect emergence. It is thus important to perform relevant tests that includes sensitive life-stages, such as metamorphosis, to fully understand the toxic effects on aquatic insects and the potential cascading effects on terrestrial ecosystems. In this study we evaluated the impact of metal contamination on timing and success of adult insect emergence by exposing chironomid (Chironomus riparus) larvae to a gradient of Pb/Zn contaminated sediment. We also investigated sex-differences in accumulation pattern of metals. Fewer adults emerged from treatments with high metal exposure compared to reference treatments and the emergence was also delayed. However, metal contamination mostly affected the survival of insect larvae, and had limited effect on metamorphosis. Males accumulated slightly higher concentrations of Pb than females, but due to their smaller sizes the individual and total flux of Pb, but also Zn, was still higher from females. The total flux of Pb, but not Zn, to terrestrial ecosystems increased with higher sediment exposure. Thus, terrestrial insectivores will be subjected to different pollution regimes depending on sediment contamination patterns, experience reduced food availability and possibly a mismatch between food availability and dietary needs due to delayed emergence.
|
|
| 6. |
- Lidman, Johan, et al.
(author)
-
Effect of recent mining activities on sediment properties and toxicity to freshwater organisms
-
Other publication (other academic/artistic)abstract
- The release of toxic metals from local mining activities often represents a serious environmental hazard, impacting nearby lake ecosystems and resulting in contamination that vary in both space and time. Here, we present dated (210Pb and 137Cs) sediment core results to reconstruct spatial and temporal patterns in trace element deposition in lakes (two clearing ponds and one lake) located in the vicinity of a closed lead (Pb) and zinc (Zn) mine in northern Sweden. All lakes displayed increased Pb and Zn concentrations after the mining operation started (1943), whereas the organic matter content declined. Lakes used as clearing ponds received higher inputs of Pb, with a sharp increase in Pb concentration occurring when tailing ponds were constructed (1952, 1965 and 1978, respectively) and a decline after the ceasing of the activities (2001). Zn concentrations increased gradually from the mining operation started to present time. The probable effect concentration quotient (PEC-Q) predicted severe toxic effects throughout the mining and post-mining period, but with spatial and temporal differences. Although PEC-Q decreased during post-mining conditions due to reduced Pb concentrations and increased organic matter inflow to the lakes, sediment Pb concentrations were still >10 times higher than during pre-mining conditions. Our results indicate a lake-specific recovery, with slower recovery in lakes used as clearing-ponds. This study highlights the spatial and temporal heterogeneity of local impact from mining activities, both in metal load and sediment properties, leading to lake-specific ecosystem responses and recovery to metal contamination.
|
|
| 7. |
- Lidman, Johan, 1988-
(author)
-
Metals take flight : Transport and effects across ecosystems
- 2021
-
Doctoral thesis (other academic/artistic)abstract
- Metal contamination can have severe toxic effects in the ecosystems, resulting in loss of biodiversity, reduced abundance of organisms, and loss of ecosystem services. Traditionally, aquatic ecosystems have been regarded as a sink of metal contamination. However, lakes could also act as a source, as metals can be transported by emerging aquatic insects from the aquatic to the terrestrial ecosystem. The consequence of this transport for terrestrial organisms has previously gained little focus. In this thesis, I study metal contamination transport and toxic effects on metal exposed aquatic invertebrates and the terrestrial insectivorous bird, pied flycatcher (Ficedula hypoleuca), in aquatic and terrestrial environments contaminated by metals from a closed lead (Pb) and zinc (Zn) mine. Studied lakes adjacent to the mine all displayed elevated metal concentrations from the start of the mining operation, but with different temporal and spatial patterns with lakes used as part of the mining activity even more affected. Factors affecting metal toxicity, such as organic matter concentration in lakes, varied during the mining and post-mining period, indicating fluctuating toxicity despite similar metal concentrations. The contamination level and toxicity risk are still high 15 years after closure of the mine, but ecosystems are starting to recover. Despite high metal concentrations in lake water and sediment, no effect on invertebrate abundance or composition of aquatic invertebrates was observed. However, when focusing on metamorphosis, proportionally fewer insects emerged from more contaminated lakes. In contrast, in lab mesocosm was no effect on metamorphosis observed of non-biting midges (Chironomus riparus), although larval survival decreased, and emergence was delayed at higher metal concentrations in sediments. Emerging adult insects transported a significant amount of metals to terrestrial ecosystems, observed both in the lab and in the field. Emerging aquatic insect and ants were major dietary metal exposure routes for pied flycatcher’s nestlings. Thus, aquatic-derived metals can influence terrestrial consumers, especially in riparian zones of contaminated lakes where availability of aquatic insects is high. Increasing accumulation of Pb has been observed to reduce hemoglobin (Hb) levels in birds. Despite elevated Pb concentrations in nestling blood in contaminated environments, nestling Hb levels, used also as indicator of nestling health, was more affected by availability of different prey than Pb levels in the blood, where availability of aquatic insects and aerial terrestrial insect had positive impact on nestling health. Overall, this thesis show that metal contamination of aquatic ecosystems also influences terrestrial organisms by decreasing their food availability and increasing metal exposure via diets. Thus, potential effects on terrestrial systems should to larger extent be included when studying aquatic contaminants. Further, indirect effects and metal bioavailability could alter the toxic effects on metal-exposed organism and should be included to accurately estimate direct toxic effects.
|
|
