| 1. |
- Andersson, Gustav, et al.
(författare)
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Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival : validatory study of two independent patient cohorts
- 2014
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Ingår i: BMC Urology. - : BioMed Central (BMC). - 1471-2490. ; 14:1, s. 36-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guerin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts. Methods: Immunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS). Results: Ezrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression. Conclusions: The results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.
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| 2. |
- 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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| 3. |
- Elmqvist, Thomas, et al.
(författare)
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Urban tinkering
- 2018
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Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4065 .- 1862-4057. ; 13:6, s. 1549-1564
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Tidskriftsartikel (refereegranskat)abstract
- Cities are currently experiencing serious, multifaceted impacts from global environmental change, especially climate change, and the degree to which they will need to cope with and adapt to such challenges will continue to increase. A complex systems approach inspired by evolutionary theory can inform strategies for policies and interventions to deal with growing urban vulnerabilities. Such an approach would guide the design of new (and redesign of existing) urban structures, while promoting innovative integration of grey, green and blue infrastructure in service of environmental and health objectives. Moreover, it would contribute to more flexible, effective policies for urban management and the use of urban space. Four decades ago, in a seminal paper in Science, the French evolutionary biologist and philosopher Francois Jacob noted that evolution differs significantly in its characteristic modes of action from processes that are designed and engineered de novo (Jacob in Science 196(4295):1161-1166, 1977). He labeled the evolutionary process tinkering, recognizing its foundation in the modification and molding of existing traits and forms, with occasional dramatic shifts in function in the context of changing conditions. This contrasts greatly with conventional engineering and design approaches that apply tailor-made materials and tools to achieve well-defined functions that are specified a priori. We here propose that urban tinkering is the application of evolutionary thinking to urban design, engineering, ecological restoration, management and governance. We define urban tinkering as:A mode of operation, encompassing policy, planning and management processes, that seeks to transform the use of existing and design of new urban systems in ways that diversify their functions, anticipate new uses and enhance adaptability, to better meet the social, economic and ecological needs of cities under conditions of deep uncertainty about the future.This approach has the potential to substantially complement and augment conventional urban development, replacing predictability, linearity and monofunctional design with anticipation of uncertainty and non-linearity and design for multiple, potentially shifting functions. Urban tinkering can function by promoting a diversity of small-scale urban experiments that, in aggregate, lead to large-scale often playful innovative solutions to the problems of sustainable development. Moreover, the tinkering approach is naturally suited to exploring multi-functional uses and approaches (e.g., bricolage) for new and existing urban structures and policies through collaborative engagement and analysis. It is thus well worth exploring as a means of delivering co-benefits for environment and human health and wellbeing. Indeed, urban tinkering has close ties to systems approaches, which often are recognized as critical to sustainable development. We believe this concept can help forge much-closer, much-needed ties among engineers, architects, evolutionary ecologists, health specialists, and numerous other urban stakeholders in developing innovative, widely beneficial solutions for society and contribute to successful implementation of SDG11 and the New Urban Agenda.
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| 4. |
- Falk Erhag, Hanna, et al.
(författare)
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Concluding Remarks
- 2022
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Ingår i: A Multidisciplinary Approach to Capability in Age and Ageing. - Chem : Springer. - 9783030780654 ; 18:2, s. 143-144
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Havervall, Sebastian, et al.
(författare)
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Robust humoral and cellular immune responses and low risk for reinfection at least 8 months following asymptomatic to mild COVID-19
- 2022
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 291:1, s. 72-80
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Tidskriftsartikel (refereegranskat)abstract
- Background: Emerging data support detectable immune responses for months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination, but it is not yet established to what degree and for how long protection against reinfection lasts.Methods: We investigated SARS-CoV-2-specific humoral and cellular immune responses more than 8 months post-asymptomatic, mild and severe infection in a cohort of 1884 healthcare workers (HCW) and 51 hospitalized COVID-19 patients. Possible protection against SARS-CoV-2 reinfection was analyzed by a weekly 3-month polymerase chain reaction (PCR) screening of 252 HCW that had seroconverted 7 months prior to start of screening and 48 HCW that had remained seronegative at multiple time points.Results: All COVID-19 patients and 96% (355/370) of HCW who were anti-spike IgG positive at inclusion remained anti-spike IgG positive at the 8-month follow-up. Circulating SARS-CoV-2-specific memory T cell responses were detected in 88% (45/51) of COVID-19 patients and in 63% (233/370) of seropositive HCW. The cumulative incidence of PCR-confirmed SARS-CoV-2 infection was 1% (3/252) among anti-spike IgG positive HCW (0.13 cases per 100 weeks at risk) compared to 23% (11/48) among anti-spike IgG negative HCW (2.78 cases per 100 weeks at risk), resulting in a protective effect of 95.2% (95% CI 81.9%-99.1%).Conclusions: The vast majority of anti-spike IgG positive individuals remain anti-spike IgG positive for at least 8 months regardless of initial COVID-19 disease severity. The presence of anti-spike IgG antibodies is associated with a substantially reduced risk of reinfection up to 9 months following asymptomatic to mild COVID-19.
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| 6. |
- Isacs, Lina, PhD, et al.
(författare)
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'I didn't count "willingness to pay" as part of the value' : Monetary valuation through respondents' perspectives
- 2024
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Ingår i: Environmental Values. - : Sage Publications. - 0963-2719 .- 1752-7015. ; 33:2, s. 163-188
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Tidskriftsartikel (refereegranskat)abstract
- A frequent justification in the literature for using stated preference methods (SP) is that they are the only methods that can capture the so-called total economic value (TEV) of environmental changes to society. Based on follow-up interviews with SP survey respondents, this paper addresses the implications of that argument by shedding light on the construction of TEV, through respondents' perspective. It illuminates the deficiencies of willingness to pay (WTP) as a measure of value presented as three aggregated themes considering respondents' unintentionality, their retraction once they understood that their WTP could be decisive in cost-benefit analysis and the inherent incompleteness of WTP. We discuss why the TEV discourse persists, how it conceals rather than reveals broader notions of value and in what ways our results support the development of alternative approaches that truly endorse plurality in environmental valuation and decision-making.
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| 7. |
- Isacs, Lina, PhD, et al.
(författare)
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I didn't count "willingness to pay" as part of the value' : monetary valuation through stated preference study respondents' perspective
- 2023
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Ingår i: Environmental Values. - : White Horse Press. - 0963-2719 .- 1752-7015.
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Tidskriftsartikel (refereegranskat)abstract
- A frequent justification in the literature for using stated preference methods (SP) is that they are the only methods that can capture the so-called total economic value (TEV) of environmental changes to society. Based on follow-up interviews with SP survey respondents, this paper addresses the implications of that argument by shedding light on the construction of TEV, through respondents’ perspective. It illuminates the deficiencies of willingness to pay (WTP) as a measure of value, presented as three aggregated themes considering respondents’ unintentionality, their retraction once they understood that their WTP could be decisive in cost-benefit analysis and the inherent incompleteness of WTP. We discuss why the TEV discourse persists, how it conceals rather than reveals broader notions of value and in what ways our results support the development of alternative approaches that truly endorse plurality in environmental valuation and decision making.
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| 8. |
- Ndegwa, Nelson, et al.
(författare)
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Gastric Microbiota in a Low-Helicobacter pylori Prevalence General Population and Their Associations With Gastric Lesions
- 2020
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Ingår i: Clinical and Translational Gastroenterology. - : LIPPINCOTT WILLIAMS & WILKINS. - 2155-384X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:Non-Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity.METHODS:In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota.RESULTS:Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non-H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori-negative group had the highest microbial diversity (Shannon index) compared with the H. pylori-positive group (P = 0.001).DISCUSSION:In this low-H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.
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| 9. |
- Regnell Andersson, Sofia
(författare)
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Tuning the polylactide hydrolysis rate without introducing new migrants
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The possibility to control and tune the hydrolytic degradation rate of polylactide without introducing any new degradation products was investigated by subjecting polylactide with cyclic or linear oligolactic acid additives, and a stereocomplex between the L- and D-enantiomers of polylactide to hydrolytic degradation at 37 and 60 °C for up to 39 weeks. The degradation was monitored by measuring mass loss, molar mass changes, water uptake, changes of surface structure, crystallinity and thermal properties. The degradation product pattern was followed through pH measurements and by electrospray ionization-mass spectrometry (ESI-MS). Rapid migration of additives from the material into the aging medium was observed in the case of the more hydrophilic linear oligolactic acid additives. The mass loss at 37 °C was generally 10-20 % greater for the material containing linear additives instead of cyclic additives. The hydrolysis accelerating effect of the linear additives may be counteracted by the facilitated crystal formation of the short chains. Micrographs showed formation of holes on the surface of the material containing linear additives during degradation. This may be a result of migration of phase separated linear additives. Phase separation might take place in the material as the crystallinity increases. The stereocomplex had a higher hydrolytic stability, which is explained by the strong interactions between the complementary chain structures. At 37 °C, the observed mass loss was generally 15 % lower for the stereocomplex compared to the material containing the cyclic additives. However, a larger amount of short hydroxy acids was released from the stereocomplex material, as shown by the large pH drop and the degradation product pattern analysed using ESI-MS. This can be explained by increased intermolecular stereocomplex crystallisation, which results in a larger number of tie-chains between crystals which are susceptible to hydrolysis and facilitate the formation of shorter hydrolysis products. Hydrolysis at 60 °C, i.e. above the glass transition temperature, was drastically faster and the differences between the materials were not as obvious as at the lower temperature. A large advantage using different forms of lactide or lactic acid as additives is that no new migrants are introduced into the degradation product pattern.
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| 10. |
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