| 1. |
- Campbell, Brittany B., et al.
(författare)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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| 2. |
- Durcik, Martina, et al.
(författare)
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New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:6, s. 3968-3994
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Tidskriftsartikel (refereegranskat)abstract
- A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.
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| 3. |
- Elvin-Nowak, Ylva M. S., et al.
(författare)
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Intimate partner violence and negative health consequences: A cross-sectional study among women in a regional sample in Sweden
- 2023
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Ingår i: Scandinavian Journal of Public Health. - : SAGE PUBLICATIONS LTD. - 1403-4948 .- 1651-1905. ; 51:4, s. 636-643
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intimate partner violence (IPV) is a global health problem of enormous proportions. However, little is known about the prevalence or health consequences of IPV among women in Stockholm, Sweden, a city characterised by high levels of gender equality that hosts a large population of people born outside Europe. Aims: This study aimed to assess the prevalence of exposure to physical, psychological and sexual IPV and its associated background factors and health outcomes. Methods: This was a cross-sectional study employing a survey containing questions about the previous years exposure to IPV that was distributed to 35 midwifery clinics in Stockholm during the autumn of 2020. Any woman who visited any of these midwifery clinics during these two months was eligible to participate. Results: A total of 2239 women answered the questionnaire, of whom 25.1% reported having been subjected to IPV at some point during their life and 8.7% during the previous year. The most common ongoing exposure was psychological violence, which was reported by 6.6% of the women. Women living with IPV reported poorer self-rated general health and more recurring health symptoms and depression than unexposed women. Conclusions: Exposure to IPV is common and is associated with depression, lower general well-being and somatic health problems.
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