| 1. |
- 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.
|
|
| 2. |
- Henriksson, Martin, et al.
(författare)
-
Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv
- 2020
-
Ingår i: BJS Open. - : JOHN WILEY & SONS LTD. - 2474-9842. ; 4:1, s. 109-117
-
Tidskriftsartikel (refereegranskat)abstract
- Background Consistent data on clinical features, treatment modalities and long-term survival in patients with hepatocellular carcinoma (HCC) using nationwide quality registers are lacking. This study aimed to describe treatment patterns and survival outcomes in patients diagnosed with HCC using a national maintained database. Methods Characteristics and treatment patterns in patients diagnosed with HCC and registered in the national register of liver and bile duct tumours (SweLiv) between 2009 and 2016 were reviewed. Overall survival (OS) was estimated using Kaplan-Meier analysis and the log rank test to compare subgroups for clinical features, treatment modalities and outcomes according to the year of treatment. Results A total of 3376 patients with HCC were registered over 8 years, 246 (7 center dot 3 per cent) of whom underwent transplantation. Some 501 (14 center dot 8 per cent) and 390 patients (11 center dot 6 per cent) had resection and ablation as primary treatment. Transarterial chemoembolization and systemic sorafenib treatment were intended in 476 (14 center dot 1 per cent) and 426 patients (12 center dot 6 per cent) respectively; the remaining 1337 (39 center dot 6 per cent) were registered but referred for best supportive care (BSC). The 5-year survival rate was approximately 75 per cent in the transplantation group. Median OS was 4 center dot 6 (i.q.r. 2 center dot 0 to not reached) years after resection and 3 center dot 1 (2 center dot 3-6 center dot 7) years following ablation. In patients referred for palliative treatment, median survival was 1 center dot 4 (0 center dot 8-2 center dot 9), 0 center dot 5 (0 center dot 3-1 center dot 2) and 0 center dot 3 (0 center dot 1-1 center dot 0) years for the TACE, sorafenib and BSC groups respectively (P amp;lt; 0 center dot 001). Median survival was 0 center dot 9 years for the total HCC cohort in 2009-2012, before publication of the Swedish national treatment programme, increasing to 1 center dot 4 years in 2013-2016 (P amp;lt; 0 center dot 001). Conclusion The survival outcomes reported were in line with previous results from smaller cohorts. The introduction of national guidelines may have contributed to improved survival among patients with HCC in Sweden.
|
|
| 3. |
- Kristiansen, Ingela, et al.
(författare)
-
Clinical characteristics, long-term complications and health related quality of life (HRQoL) in children and young adults treated for low-grade astrocytoma in the posterior fossa in childhood
- 2019
-
Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 142:1, s. 203-210
-
Tidskriftsartikel (refereegranskat)abstract
- Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL.A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5-19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36).Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance.The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.
|
|
| 4. |
- Rydén, Lars, et al.
(författare)
-
ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD
- 2013
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:39, s. 3035-3087
-
Tidskriftsartikel (refereegranskat)abstract
- This is the second iteration of the European Society of Cardiology (ESC) and European Association for the Study of Diabetes (EASD) joining forces to write guidelines on the management of diabetes mellitus (DM), pre-diabetes, and cardiovascular disease (CVD), designed to assist clinicians and other healthcare workers to make evidence-based management decisions. The growing awareness of the strong biological relationship between DM and CVD rightly prompted these two large organizations to collaborate to generate guidelines relevant to their joint interests, the first of which were published in 2007. Some assert that too many guidelines are being produced but, in this burgeoning field, five years in the development of both basic and clinical science is a long time and major trials have reported in this period, making it necessary to update the previous Guidelines.
|
|
| 5. |
- Strömberg, Per M., et al.
(författare)
-
Citizen monitoring in environmental disclosure : An economics perspective
- 2024
-
Ingår i: Journal of Environmental Management. - : Elsevier. - 0301-4797 .- 1095-8630. ; 356
-
Tidskriftsartikel (refereegranskat)abstract
- Criticism is mounting that market-led and state-led initiatives for environmental impact disclosure are too limited in scope and that they rest on too strong assumptions about the quality and impartiality of monitoring and enforcement, with resulting insufficient effect on environmental sustainability. It has been proposed that citizen monitoring may contribute to counteract this void. However, to our knowledge, policy analysis in general and economics in particular has not paid much attention to this role of citizen monitoring. This paper aims to bridge that gap from an economics lens, by exploring the dynamics of disclosing local environmental impact and the potential role of citizen monitoring in environmental policy. To this end, the paper addresses monopolistic versus pluralistic environmental disclosure, letting citizen monitoring represent the latter. The study uses the mining industry as an illustrative case, because of that sector's particular transparency challenges in international value chains, typically with strong negative local environmental impact. It is shown how pluralistic information provision such as citizen monitoring can contribute to incentivizing more reliable information provision, especially in countries with weak state institutions, which is particularly important in the case of high-risk environmental impact. The findings should be of use for shaping environmental policy, providing valuable insights for both policymakers and scholars.
|
|
| 6. |
- Strömberg, Tomas, 1966-
(författare)
-
Respiratory inductive plethysmography (RIP) : calibration, breathing pattern analysis and external CO2 dead space measurement
- 1996
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Respiratory inductive plethysmography (RIP) is an important tool for ventilatory monitoring in research studies because it has minimal influence on the spontaneous breathing pattern and because the rib cage and abdominal contributions to the breaths are measured. RIP measures changes in rib cage and abdominal cross-sectional areas which are translated into lung volume estimates via RIP calibration against e.g., a pneumotachometer (PTM). The commercially available RIP (Respitrace ®) was used to evaluate models and methods for RIP calibration, to study changes in breathing pattern during induced bronchial obstruction in asthmatics and to improve a unique method for measuring the external CO2 dead space volume in facial visors and respiratory protective devices.Several models of the respiratory system and various methods and volume references can be used during RIP calibration. We found that conventional use of the PTM can result in large volumetric PTM errors, but with proper compensations the PTM is a useful volume reference. A linear model of the respiratory system, relating lung volume changes from the start of inspiration or expiration to rib cage and abdominal excursion from the start of respiratory motion, was the most accurate. The voluntarily preferential rib cage and abdominal breathing method for RIP calibration proved to be appropriate and robust with similar accuracy as that obtained with other methods.The spontaneous breathing pattern was recorded in asthmatics at rest and during bronchial histamine and methacholine challenges (HiCh/MeCh). The relationship between the airways' obstruction and the breathing pattern was explored. In one study, only four of eight patients showed a significant increase in minute ventilation (V'I: mean 72%) and mean inspiratory flow (VTI/TI; mean 80%) during HiCh. In another study a groupwise increase of 20% in V'I and V'TI/TI was found during repeated HiCh and repeated MeCh. However, the individual repeatability was poor. The ventilatory response did not correlate to the central or the peripheral airways' obstruction, nor to hypoxaemia or sensations of dyspnoea. Breathing pattern analysis is consequently not an adequate method for airways' obstruction monitoring during bronchial challenge. The ventilatory response appears to be the result of a complex interaction between several afferent stimuli and central ventilatory control mechanisms.Analysis of the variability of the breathing pattern components confirmed that the timing component (phase switching; inspiration/expiration) of the respiratory control system is more constant than the drive and volume function. Furthermore, the variability did not change during induced obstruction.A unique method for assessment of the external CO2 dead space volume in facial visors and respiratory protective devices was evaluated and further improved. The method was found to have sufficient accuracy (dead space measurement error ≤ 20%), provided that great concern was taken to measure the initial CO2 containing part of inspiration correctly with RIP.
|
|
| 7. |
- Strömberg, Tomas, 1966-, et al.
(författare)
-
Ventilation inhomogeneity assessed by nitrogen washout and ventilation- perfusion mismatch by capnography in stable and induced airway obstruction
- 2000
-
Ingår i: Pediatric Pulmonology. - 8755-6863 .- 1099-0496. ; 29:2, s. 94-102
-
Tidskriftsartikel (refereegranskat)abstract
- Few studies have been published on gas distribution in the lung during acute and stable airway obstruction in children. Multiple breath nitrogen (N(2)) washout is an established method for assessing ventilation inhomogeneity, while the tidal breathing capnogram may be used as an indicator of ventilation-perfusion (V(')(A)/Q) mismatch. We hypothesized that significant V(')(A)/Q mismatch is not seen in stable airway obstruction unless obstruction is severe, and that stable and induced airway obstruction of similar severity would result in different degrees of V(')(A)/Q mismatch. To test this hypothesis, we performed spirometry measurements of forced expiratory volume in 1 sec (FEV(1)), multiple breath N(2) washout, and tidal breathing capnography in 11 young patients (9-30 years) with cystic fibrosis, 37 asthmatic patients (8-18 years), and 34 healthy subjects (7-20 years). Lung function was measured at rest, after airway obstruction induced by cold dry air hyperventilation or methacholine challenge, and after beta(2)-agonist treatment. V(')(A)/Q mismatch was assessed from the slopes of the phases II and III of the capnogram. We observed a normal capnogram during stable obstruction of moderate severity despite significant ventilation inhomogeneity. In patients with severe stable obstruction and in those with induced airway obstruction significant ventilation inhomogeneity and pathological capnograms were seen. Induced airway obstruction, resulted in a more pathological capnogram than stable obstruction of similar severity. beta(2)-agonist treatment reduced ventilation inhomogeneity, but did not improve the capnogram. Our findings are compatible with the presence of an efficient pulmonary blood flow regulatory mechanism that adequately compensates for chronic ventilation inhomogeneity of moderate severity, but not for severe or sudden airway obstruction.
|
|
| 8. |
|
|
| 9. |
- Thomas, Anub Mathew, et al.
(författare)
-
Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.
- 2018
-
Ingår i: Neonatology. - : S. Karger. - 1661-7800 .- 1661-7819. ; 113:4, s. 322-330
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.OBJECTIVES: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model.METHODS: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA.RESULTS: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14.CONCLUSION: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.
|
|
