| 1. |
|
|
| 2. |
|
|
| 3. |
- Berglund, U. W., et al.
(författare)
-
Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
-
Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
|
|
| 4. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
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.
|
|
| 5. |
- Berglind, S.-A., Ehnstrom, B. and Ljungberg, H.
(författare)
-
Riparian beetles, biodiversity, and stream flow regulation - the examples of Svartån and Mjällån streams, Central Sweden
- 1997
-
Ingår i: Entomologisk Tidskrift. - : The Entomological Society of Sweden, Umeå. - 0013-886X. ; 118:4, s. 137-154
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden, 70% of running waters have been exploited for hydropower purposes. Although hydroelectric power plants in small running waters, i.e. streams, contribute only 1% of the total electric production in Sweden, and the prospects for increasing this p
|
|
| 6. |
|
|
| 7. |
- Döringer, Nora, et al.
(författare)
-
Motivational Interviewing to Prevent Childhood Obesity: A Cluster RCT
- 2016
-
Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 137:5
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective was to evaluate a manualized theory-driven primary preventive intervention aimed at early childhood obesity. The intervention was embedded in Swedish child health services, starting when eligible children were 9 to 10 months of age and continuing until the children reached age 4. METHODS: Child health care centers in 8 Swedish counties were randomized into intervention and control units and included 1355 families with 1369 infants. Over similar to 39 months, families in the intervention group participated in 1 group session and 8 individual sessions with a nurse trained in motivational interviewing, focusing on healthy food habits and physical activity. Families in the control group received care as usual. Primary outcomes were children's BMI, overweight prevalence, and waist circumference at age 4. Secondary outcomes were children's and mothers' food and physical activity habits and mothers' anthropometrics. Effects were assessed in linear and log-binominal regression models using generalized estimating equations. RESULTS: There were no statistically significant differences in children's BMI (beta = -0.11, 95% confidence interval [CI]: -0.31 to 0.08), waist circumference (beta = -0.48, 95% CI: -0.99 to 0.04), and prevalence of overweight (relative risk = 0.95, 95% CI: 0.69 to 1.32). No significant intervention effects were observed in mothers' anthropometric data or regarding mothers' and children's physical activity habits. There was a small intervention effect in terms of healthier food habits among children and mothers. CONCLUSIONS: There were no significant group differences in children's and mothers' anthropometric data and physical activity habits. There was, however, some evidence suggesting healthier food habits, but this should be interpreted with caution.
|
|
| 8. |
- Halfdansdottir, Berglind, et al.
(författare)
-
Autonomy in place of birth : a concept analysis
- 2015
-
Ingår i: Medicine, Health care and Philosophy. - : Springer Science and Business Media LLC. - 1386-7423 .- 1572-8633. ; 18:4, s. 591-600
-
Tidskriftsartikel (refereegranskat)abstract
- This article examines one of the relevant concepts in the current debate on home birth-autonomy in place of birth-and its uses in general language, ethics, and childbirth health care literature. International discussion on childbirth services. A concept analysis guided by the model of Walker and Avant. The authors suggest that autonomy in the context of choosing place of birth is defined by three main attributes: information, capacity and freedom; given the antecedent of not harming others, and the consequences of accountability for the outcome. Model, borderline and contrary cases of autonomy in place of birth are presented. A woman choosing place of birth is autonomous if she receives all relevant information on available choices, risks and benefits, is capable of understanding and processing the information and choosing place of birth in the absence of coercion, provided she intends no harm to others and is accountable for the outcome. The attributes of the definition can serve as a useful tool for pregnant women, midwives, and other health professionals in contemplating their moral status and discussing place of birth.
|
|
| 9. |
- Halfdansdottir, Berglind, et al.
(författare)
-
Maternal attitudes towards home birth and their effect on birth outcomes in Iceland : A prospective cohort study
- 2016
-
Ingår i: Midwifery. - : Elsevier BV. - 0266-6138 .- 1532-3099. ; 34, s. 95-104
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: to examine the relationship between attitudes towards home birth and birth outcomes, and whether women's attitudes towards birth and intervention affected this relationship. Design: a prospective cohort study. Setting: the study was set in Iceland, a sparsely populated island with harsh terrain, 325,000 inhabitants, high fertility and home birth rates, and less than 5000 births a year. Participants: a convenience sample of women who attended antenatal care in Icelandic health care centres, participated in the Childbirth and Health Study in 2009-2011, and expressed consistent attitudes towards home birth (n=809). Findings: of the participants, 164 (20.3%) expressed positive attitudes towards choosing home birth and 645 (79.7%) expressed negative attitudes. Women who had a positive attitude towards home birth had significantly more positive attitudes towards birth and more negative attitudes towards intervention than did women who had a negative attitude towards home birth. Of the 340 self-reported low-risk women that answered questionnaires on birth outcomes, 78 (22.9%) had a positive attitude towards home birth and 262 (77.1%) had a negative attitude. Oxytocin augmentation (19.2% (n=15) versus 39.1% (n=100)), epidural analgesia (19.2% (n=15) versus 33.6% (n=88)), and neonatal intensive care unit admission rates (0.0% (n=0) versus 5.0% (n=13)) were significantly lower among women who had a positive attitude towards home birth. Women's attitudes towards birth and intervention affected the relationship between attitudes towards home birth and oxytocin augmentation or epidural analgesia. Key conclusions and implications for practice: the beneficial effect of planned home birth on maternal outcome in Iceland may depend to some extent on women's attitudes towards birth and intervention. Efforts to de-stigmatise out-of-hospital birth and de-medicalize women's attitudes towards birth might increase women's use of health-appropriate birth services.
|
|
| 10. |
- Hardarson, Johann P. P., et al.
(författare)
-
Appraisals of Social Trauma and Their Role in the Development of Post-Traumatic Stress Disorder and Social Anxiety Disorder
- 2023
-
Ingår i: Behavioral Sciences. - : MDPI. - 2076-328X. ; 13:7
-
Tidskriftsartikel (refereegranskat)abstract
- Cognitive theories of post-traumatic stress disorder (PTSD) feature appraisal of trauma as a critical factor in the development and maintenance of the disorder. Here we explored appraisals of social trauma (severe rejection or humiliation). Participants were outpatients with social anxiety disorder (SAD) and clinically significant PTSD symptoms (PTSS) after social trauma (n = 15); two clinical control groups of either SAD (n = 32) or obsessive-compulsive disorder (OCD; n = 13); and a control group with no diagnoses (n = 38). Measures included a clinical interview to assess social trauma and related open-ended appraisals and the Posttraumatic Cognitions Inventory (PTCI). Raters blind to group assignment performed content analyses of appraisals. Results showed that the PTSS group scored significantly higher than either clinical group on the PTCI SELF subscale. Only the SELF subscale predicted a diagnosis of both PTSS and SAD. All but one PTSS participant reported primarily negative beliefs about their social trauma, and the most common categories were flawed self and others are critical or cruel. Post-traumatic appraisals implicated in the course of PTSD are significant in how individuals respond to social trauma, with negative self-cognitions linked to both PTSS and SAD.
|
|
