| 1. |
- Tomic, Tajana Tesan, et al.
(författare)
-
MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
-
Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
-
Tidskriftsartikel (refereegranskat)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
|
|
| 2. |
- Chen, Yihong, et al.
(författare)
-
Evidence for a protective role of placental growth factor in cardiovascular disease
- 2020
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:572
-
Tidskriftsartikel (refereegranskat)abstract
- Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.
|
|
| 3. |
- Grossmann, Benjamin, et al.
(författare)
-
Patient-controlled Sedation During Flexible Bronchoscopy : A Randomized Controlled Trial
- 2020
-
Ingår i: Journal of Bronchology & Interventional Pulmonology. - : Lippincott Williams & Wilkins. - 1944-6586 .- 1948-8270. ; 27:2, s. 77-85
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Patient-controlled sedation (PCS) is a documented method for endoscopic procedures considered to facilitate early recovery. Limited data have been reported, however, on its use during flexible bronchoscopy (FB).Materials and Methods: This study hypothesized that PCS with propofol during FB would facilitate early recovery, with similar bronchoscopist and patient satisfaction compared with nurse-controlled sedation (NCS) with midazolam. A total of 150 patients were randomized 1:1:1 into a control group (premedication with morphine-scopolamine and NCS with midazolam), PCS-MS group (premedication with morphine-scopolamine and PCS with propofol), and PCS-G group (premedication with glycopyrronium and PCS with propofol).Results: The procedures included transbronchial biopsy, transbronchial needle aspiration, cryotherapy/biopsy, and/or multistation endobronchial ultrasound. FB duration values in median (range) were 40 (10 to 80), 39 (12 to 68), and 44 (10 to 82) minutes for the groups NCS, PCS-MS, and PCS-G, respectively. An overall 81% of the patients in the combined PCS groups were ready for discharge (modified Post Anaesthetic Discharge Scoring System, score 10) 2 hours after bronchoscopy compared with 40% in the control group (P<0.0001). Between PCS groups, 96% of the PCS-G group patients were ready for discharge compared with 65% in the PCS-MS group (P=0.0002) at 2 hours. Bronchoscopists’ and patients’ satisfaction scores were high in all groups. Postdischarge quality scores showed no differences among the groups.Conclusion: PCS with propofol during FB is feasible, as it shortened recovery time without compromising procedure conditions for bronchoscopists or patients. A rapid postsedation stabilization of vital signs facilitates surveillance before the patient leaves the hospital.
|
|
| 4. |
- Grossmann, Benjamin, et al.
(författare)
-
Patient-controlled sedation with propofol for endoscopic procedures : A cost analysis
- 2020
-
Ingår i: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 64:1, s. 53-62
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundPatient‐controlled sedation (PCS) with propofol accompanied by a bedside nurse anaesthetist is an alternative sedation method for endoscopic procedures compared with midazolam administered by a nurse or endoscopist. Increasing costs in health care demands an economic perspective when introducing alternative methods. We applied a hospital perspective on a cost analysis comparing different methods of sedation and the resource use that were expected to affect cost differences related to the sedation.MethodsBased on two randomised previous studies, the direct costs were determined for different sedation methods during two advanced endoscopic procedures: endoscopic retrograde cholangiopancreatography (ERCP) and flexible bronchoscopy including endobronchial ultrasound. ERCP comparisons were made between midazolam sedation by the endoscopic team, PCS with a bedside nurse anaesthetist and propofol sedation administered by a nurse anaesthetist. Bronchoscopy comparisons were made between midazolam sedation by the endoscopic team and PCS with a bedside nurse anaesthetist, categorised by premedication morphine‐scopolamine or glycopyrronium.ResultsPropofol PCS with a bedside nurse anaesthetist resulted in lower costs per patient for sedation for both ERCP (233 USD) and bronchoscopy (premedication morphine‐scopolamine 267 USD, premedication glycopyrronium 269 USD) compared with midazolam (ERCP 425 USD, bronchoscopy 337 USD). Aborted procedures that needed to be repeated and prolonged hospital stays significantly increased the cost for the midazolam groups.ConclusionPropofol PCS with a bedside nurse anaesthetist reduces the direct sedation costs for ERCP and bronchoscopy procedures compared with midazolam sedation.
|
|
| 5. |
- Tomas, Lukas, et al.
(författare)
-
Low Levels of CD4+CD28null T Cells at Baseline Are Associated With First-Time Coronary Events in a Prospective Population-Based Case-Control Cohort
- 2020
-
Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - 1524-4636. ; 40:2, s. 426-436
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: CD4+CD28null T cells have been shown to be associated with recurrent coronary events and suggested as potential biomarker and therapeutic target. It is unknown whether CD4+CD28null T cells associate with first-time cardiovascular events. We examined CD4+CD28null T cells in a prospective population-based cohort and in patients with advanced atherosclerosis. Approach and Results: CD4+CD28null T cells were quantified in 272 individuals experiencing a first-time coronary event during up to 17 years of follow-up and 272 age- and sex-matched controls in a case-control study, nested within the population-based Malmö Diet and Cancer study. The highest tertile of CD4+CD28null T cells was associated with a lower incidence of first-time coronary events compared with the lowest tertile (odds ratio, 0.48 [95% CI, 0.29-0.79], P=0.004) when adjusting for Framingham risk factors. This association remained significant for events recorded after >9 years of follow-up, when most coronary events occurred, but not during the first 9 years of follow-up, despite similar odds ratio. Additionally, we analyzed CD4+CD28null T cells in 201 patients with advanced atherosclerosis undergoing carotid endarterectomy. The adjusted hazard ratio for cardiovascular events in patients with advanced atherosclerosis was 2.11 (95% CI, 1.10-4.05, P=0.024), comparing the highest with the lowest CD4+CD28null T-cell tertile.CONCLUSIONS: Our findings reveal complex associations between CD4+CD28null T cells and cardiovascular disease. Although we confirm the reported positive associations with an adverse prognosis in patients with already established disease, the opposite associations with first-time coronary events in the population-based cohort may limit the clinical use of CD4+CD28null T cells.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Andell, Pontus, et al.
(författare)
-
Neighborhood socioeconomic status and aortic stenosis : A Swedish study based on nationwide registries and an echocardiographic screening cohort
- 2020
-
Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 318, s. 153-159
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Aortic stenosis (AS) is the most common valvular heart disease in developed countries, confers high mortality in advanced cases, but can effectively be reversed using endovascular or open-heart surgery. We evaluated the association between AS and neighborhood socioeconomic status (NSES). Methods: We used Swedish population-based nationwide registers and an echocardiography screening cohort during the study period 1997–2014. NSES was determined by an established neighborhood deprivation index composed of education, income, unemployment, and receipt of social welfare. Multilevel adjusted logistic regression models determined the association between NSES and incident AS (according to ICD-10 diagnostic codes). Results: The study population of men and women (n=6,641,905) was divided into individuals living in high (n = 1,608,815 [24%]), moderate (n = 3,857,367 [58%]) and low (n = 1,175,723 [18%]) SES neighborhoods. There were 63,227 AS cases in total. Low NSES (versus high) was associated with a slightly increased risk of AS (OR 1.06 [95% CI 1.03–1.08]) in the nationwide study population. In the echocardiography screening cohort (n = 1586), the association between low NSES and AS was markedly stronger (OR: 2.73 [1.05–7.12]). There were more previously undiagnosed AS cases in low compared to high SES neighborhoods (3.1% versus 1.0%). Conclusions: In this nationwide Swedish register study, low NSES was associated with a slightly increased risk of incident AS. However, the association was markedly stronger in the echocardiography screening cohort, which revealed an almost three-fold increase of AS among individuals living in low SES neighborhoods, possibly indicating an underdiagnosis of AS among these individuals.
|
|
| 9. |
- Andreasson, Fredrik, et al.
(författare)
-
Age differences in night-time metabolic rate and body temperature in a small passerine
- 2020
-
Ingår i: Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology. - : Springer Science and Business Media LLC. - 0174-1578. ; 190, s. 349-359
-
Tidskriftsartikel (refereegranskat)abstract
- Spending the winter in northern climes with short days and cold ambient temperatures (Ta) can be energetically challenging for small birds that have high metabolic and heat loss rates. Hence, maintaining body temperature (Tb) in Ta below thermoneutrality can be energetically costly for a small bird. We still know little about how increased heat production below thermoneutrality affects the level at which Tb is maintained, and if these patterns are age specific. To test this, we measured subcutaneous body temperature (Ts) and resting metabolic rate (RMR) simultaneously in blue tits (Cyanistes caeruleus) during winter nights in Ta’s ranging from 25 to − 15 °C. RMR increased below the lower critical temperature (LCT, estimated at 14 °C) and was 6% higher in young (birds in their first winter) compared to old birds (birds in their second winter or older). The higher RMR was also mirrored in higher Ts and thermal conductance (C) in young birds, which we suggest could be caused by age differences in plumage quality, likely driven by time constraints during moult. Reduction in nightly predicted Tb was modest and increased again at the coldest ambient temperatures, suggesting that either heat retention or heat production (or both) improved when Ta reached levels which are cold by the standards of birds in our population. Our results show that levels of heat production and Tb can be age specific. Further studies should address age-specific differences on quality, structure, and thermal conductivity of plumage more explicitly, to investigate the role of variation in insulation in age-linked metabolic phenotypes.
|
|
| 10. |
- Andreasson, Fredrik, et al.
(författare)
-
Avian Reproduction in a Warming World
- 2020
-
Ingår i: Frontiers in Ecology and Evolution. - : Frontiers Media SA. - 2296-701X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Weather influences both the distribution and life-history strategies of birds. Temperature ranks amongst the more important weather parameters in this regard since warming springs in temperate and high latitudes and more frequent heat-waves globally have caused major changes in breeding phenology and negatively affected adult and juvenile survival, respectively. Both long-term and stochastic changes in temperature can have fundamental consequences for avian reproduction even when the effects are not lethal, such as via thermal constraints on parental provisioning and chick growth. To date, most of what we know about temperature effects on nestling development and parental effort during reproduction is based on correlative data. In addition, an increasing amount of evidence indicates that temperature change also significantly affects birds that breed in cooler temperate areas, which so far has been somewhat overlooked. Therefore, in this perspective piece, we outline the existing literature on temperature effects on nestling development and parental behavior, with an emphasis on what needs to be done to address the causal effects of temperature change on avian reproduction under climate change. We finish by providing an outlook over future avenues of research, and give suggestions of some specific areas that might be especially promising in developing this field of research.
|
|
