| 1. |
|
|
| 2. |
- Bonagas, Nadilly, et al.
(författare)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
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.
|
|
| 3. |
- 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.
|
|
| 4. |
|
|
| 5. |
- Gustafsson, Christine, 1967-, et al.
(författare)
-
Trust leading to hope - the signification of meaningful encounters in Swedish healthcare. The narratives of patients, relatives and healthcare staff
- 2013
-
Ingår i: International Practice Development Journal. - 2046-9292. ; 3:1, s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The fact that patients and relatives experience poor healthcare encounters is evident in the number of complaints to patients’ advisory committees, and from studies and statistics. Looking at ‘the other side of the coin’, research into good caring encounters experienced as meaningful encounters in healthcare is scarce.Aim: To illuminate the signification of meaningful encounters in healthcare. 124 narratives from patients, relatives and healthcare staff regarding experiences of meaningful encounters in Swedish healthcare were analysed using a phenomenological hermeneutic research method.Conclusions: The results indicate that a meaningful encounter means gratefulness, is founded on trust, cooperation and courage, and results in self-trust through wellbeing, increased understanding and life-changing insights. The encounters have given insight into, and increased understanding of, the patient’s own life, the families’ lives, and/or healthcare professionals’ lives. With this, and awareness of the importance and power of meaningful encounters, healthcare staff might use a meaningful encounter as a powerful instrument in caring.Implications for practice:For patients and relatives, trust derived from meaningful encounters in healthcare leads to self-trustCaring within healthcare consisting of meaningful encounters, ‘the other side of the coin’ gives important knowledge that could facilitate improvements in healthcare staff’s encounters with patients and relatives, and also enrichment in their own professional developmentIncreased understanding and awareness of the power of meaningful encounters can be discussed in terms of patient safety
|
|
| 6. |
- Gustafsson, Ingrid, et al.
(författare)
-
The nurse anesthetists' adherence to Swedish national recommendations to maintain normothermia in patients during surgery
- 2017
-
Ingår i: Journal of Perianesthesia Nursing. - : Elsevier. - 1089-9472 .- 1532-8473. ; 32:5, s. 409-418
-
Tidskriftsartikel (refereegranskat)abstract
- PurposeThe aim of this study was to determine if nurse anesthetists (NAs) have access, knowledge, and adhere to recommended guidelines to maintain normal body temperature during the perioperative period.DesignA descriptive survey design.MethodsQuestionnaires were sent to heads of the department (n = 56) and NAs in the operating departments in Sweden.FindingThe level of access to the recommendations is high, but only one third of the operating departments have included the recommendations in their own local guidelines. The NAs' adherence was low, between 5% and 67%, and their knowledge levels were 57% to 60%.ConclusionsA high level of knowledge, access, and adherence are important for the organization of operating departments to prevent barriers against implementation of new recommendations or guidelines. There are needs for education about patients' heat loss due to redistribution and clear recommendations.
|
|
| 7. |
- Gustafsson, Lena-Karin, 1966-, et al.
(författare)
-
The meaningful encounter : Patient and next of kin stories about their experience of meaningful encounters in health care
- 2013
-
Ingår i: Nursing Inquiry. - : Wiley. - 1320-7881 .- 1440-1800. ; 20:4, s. 363-371
-
Tidskriftsartikel (refereegranskat)abstract
- This study focuses on the meaningful encounters of patients and next of kin, seen from their perspective. Identifying the attributes within meaningful encounters is important for increased understanding of caring and to expand and develop earlier formulated knowledge about caring relationships. Caring theory about the caring relationship and provided a point of departure for the study. The aim of this study was to illuminate the meaningful encounter in health care contexts narrated by patients and next of kin. A qualitative explorative design with a hermeneutic narrative approach was used to analyze and interpret the written narratives. Phases were: Naïve interpretation, structure analysis on two different levels a) analysis of narrative structure b) analysis of deep structure through metaphors and finally a dialectic interpretation. In the narratives the meaning of the meaningful encounter was sharing, a nourishing fellowship, common responsibility and coming together experienced as safety and warmth and gives, by extension, life changing moments, a healing force and dissipated insight. The meaningful encounter can be seen as a complex phenomenon that has different attributes. Understanding the meaningful encounter will enable nurses to plan and provide professional care, based on caring science focusing on patient and next of kin experience.
|
|
| 8. |
- Kilpeläinen, Tuomas O, et al.
(författare)
-
Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
|
|
| 9. |
- Margaryan, Ashot, et al.
(författare)
-
Population genomics of the Viking world
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 585:7825, s. 390-396
-
Tidskriftsartikel (refereegranskat)abstract
- The maritime expansion of Scandinavian populations during the Viking Age (about ad750–1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
|
|
| 10. |
- Nyholm, Tufve, et al.
(författare)
-
A national approach for automated collection of standardized and population-based radiation therapy data in Sweden
- 2016
-
Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 119:2, s. 344-350
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To develop an infrastructure for structured and automated collection of interoperable radiation therapy (RT) data into a national clinical quality registry. Materials and methods: The present study was initiated in 2012 with the participation of seven of the 15 hospital departments delivering RT in Sweden. A national RT nomenclature and a database for structured unified storage of RT data at each site (Medical Information Quality Archive, MIQA) have been developed. Aggregated data from the MIQA databases are sent to a national RT registry located on the same IT platform (INCA) as the national clinical cancer registries. Results: The suggested naming convention has to date been integrated into the clinical workflow at 12 of 15 sites, and MIQA is installed at six of these. Involvement of the remaining 3/15 RT departments is ongoing, and they are expected to be part of the infrastructure by 2016. RT data collection from ARIA (R), Mosaiq (R), Eclipse (TM), and Oncentra (R) is supported. Manual curation of RT-structure information is needed for approximately 10% of target volumes, but rarely for normal tissue structures, demonstrating a good compliance to the RT nomenclature. Aggregated dose/volume descriptors are calculated based on the information in MIQA and sent to INCA using a dedicated service (MIQA2INCA). Correct linkage of data for each patient to the clinical cancer registries on the INCA platform is assured by the unique Swedish personal identity number. Conclusions: An infrastructure for structured and automated prospective collection of syntactically inter operable RT data into a national clinical quality registry for RT data is under implementation. Future developments include adapting MIQA to other treatment modalities (e.g. proton therapy and brachytherapy) and finding strategies to harmonize structure delineations. How the RT registry should comply with domain-specific ontologies such as the Radiation Oncology Ontology (ROO) is under discussion.
|
|
