| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Borgenvik, Anna, 1987-, et al.
(författare)
-
Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
-
Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
-
Tidskriftsartikel (refereegranskat)abstract
- Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
|
|
| 10. |
- Burkard, T, et al.
(författare)
-
THE ASSOCIATION BETWEEN BARIATRIC SURGERY AND DUPUYTREN DISEASE: A COHORT STUDY FROM SWEDISH NATIONWIDE HEALTHCARE REGISTRIES
- 2021
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 974-975
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Dupuytren disease (DD) is multifactorial, with several genetic and environmental risk factors contributing to disease susceptibility. High body mass index, however, was suggested to be protective of DD.1 The impact of weight loss among obese patients on DD has not been assessed to date.Objectives:To assess the association between bariatric surgery and DD in a secondary care setting.Methods:We performed a propensity score (PS)-matched cohort study using data from Swedish nationwide healthcare registries (patient registry [secondary care], causes of death registry, prescribed drug registry). Patients aged 30-79 years who underwent bariatric surgery between 2006 and 2019 were matched to up to 2 obese bariatric surgery-free patients (called unexposed patients) based on their PS. PS-matching was carried out in risk set sampling to reduce selection bias, within 4 sequential cohort entry blocks to account for time trend biases. The outcome DD was defined as a diagnosis of DD in secondary care or partial or total fasciotomy of wrist or hand. After a 1-year run-in period, patients were followed in an “as-treated” approach. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CIs) of incident DD among bariatric surgery patients when compared to obese unexposed patients overall, and in subgroups of age, sex, bariatric surgery type, and by duration of follow-up.Results:A total of 34 959 bariatric surgery patients were PS-matched to 54 769 obese unexposed patients. A total of 71.6% of bariatric surgery patients were women. Bariatric surgery patients had a mean age of 45.5 years and a mean follow-up of 6.9 years. All patient characteristics in obese unexposed patients were highly similar. We observed 126 and 136 severe DD cases among bariatric surgery and obese unexposed patients, respectively. The risk of DD was significantly increased in bariatric surgery patients compared to obese unexposed patients (HR = 1.30, 95% CI 1.02-1.65). The risk of DD was higher in women (HR = 1.36, 95% CI 1.00-1.84) than in men (HR = 1.05, 95% CI 0.70-1.58). Age did not modify the risk of DD among bariatric surgery patients compared to obese unexposed patients. Malabsorptive bariatric surgery yielded an increased risk of DD when compared to obese unexposed patients (HR = 1.33, 95% CI 1.04-1.71), while restrictive bariatric surgery yielded a null result. The risk of DD increased with duration of follow-up (>5 years of follow-up: HR = 1.63, 95% CI 1.14-2.34, null result in earlier follow-up).Conclusion:Our results suggest that substantial weight loss is associated with a latent increased risk of severe DD in an obese population. This observation further strengthens current evidence that high body mass index is protective against DD. The latency of risk increase of DD after bariatric surgery may suggest that slowly adapting metabolic changes may be part of the mechanism of DD emergence.References:[1]Hacquebord JH, Chiu VY, Harness NG. The Risk of Dupuytren Surgery in Obese Individuals. J Hand Surg Am. 2017, 42: 149–55.Acknowledgements:We thank Prof. Dr. Jesper Lagergren (Karolinksa Institutet, Stockholm, Sweden) for hosting Dr. Theresa Burkard for a research stay at the Upper Gastrointestinal Surgery Group and making the data available for use. Furthermore, we thank Dr. Giola Santoni (Karolinksa Institutet, Stockholm, Sweden) for her technical support.Disclosure of Interests:None declared
|
|
| 11. |
- Burkard, T, et al.
(författare)
-
The association of bariatric surgery and Dupuytren's disease: a propensity score-matched cohort study
- 2022
-
Ingår i: The Journal of hand surgery, European volume. - : SAGE Publications. - 2043-6289. ; 47:3, s. 288-295
-
Tidskriftsartikel (refereegranskat)abstract
- We aimed to assess the association between bariatric surgery and incident Dupuytren’s disease (DD) using propensity score-matched cohort studies among Swedish nationwide healthcare registries. Patients aged 30–79 years who underwent bariatric surgery 2006–2019 were matched on their propensity scores, up to two obese bariatric surgery-free (unexposed) patients. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the risk of DD overall, in subgroups of age, sex, bariatric surgery type and duration of follow-up. Among 34,959 bariatric surgery patients and 54,769 propensity score-matched obese patients, the risk of DD was increased in bariatric surgery patients compared with obese unexposed patients (HR 1.30, 95% CI 1.02–1.65), among women (HR 1.36; 1.00–1.84); those undergoing gastric bypass (HR 1.33; 1.04–1.71) and those with >5 years follow-up (HR 1.63; 1.14–2.34). Our results suggest that substantial weight loss is associated with an increased risk of DD in an obese population. Level of evidence: III
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
- Smith, H. G., et al.
(författare)
-
Variations in the definition and perceived importance of positive resection margins in patients with colorectal cancer - an EYSAC international survey
- 2023
-
Ingår i: EJSO. - 0748-7983 .- 1532-2157. ; 49:11
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Microscopically positive resection margins (R1) are associated with poorer outcomes in patients with colorectal cancer. However, different definitions of R1 margins exist. It is unclear to what extent the definitions used in everyday clinical practice differ within and between nations. This study sought to investigate variations in the definition of R1 margins in colorectal cancer and the importance of margin status in clinical decision-making.Materials and methods: A 14-point survey was developed by members of The European Society of Surgical Oncology (ESSO) Youngs Surgeons and Alumni Club (EYSAC) Research Academy targeting all members of the multidisciplinary team (MDT) treating patients with colorectal cancer. The survey was distributed on social media, in ESSO's monthly newsletter and via national societies.Results: In total, 137 responses were received. Most respondents were from Europe (89.7%), with the majority from Denmark (56.9%). Less than 2/3 of respondents defined R1 margins as the presence of viable cancer cells <= 1 mm of the margin. Only 60% reported that subdivisions of R1 margins (primary tumour vs tumour deposit vs metastatic lymph node) are routinely available. More than 20% of respondents reported that pathology reports are not routinely reviewed at MDT meetings. Less than half of respondents considered margin status in decisionmaking for type and duration of adjuvant chemotherapy in Stage III colon cancer.Conclusion: The definitions and perceived clinical importance of microscopically positive margins in patients with colorectal cancer appear to vary. Adoption of an international dataset for pathology reporting may help to standardise current practices.
|
|
| 15. |
- Womersley, Freya C., et al.
(författare)
-
Identifying priority sites for whale shark ship collision management globally
- 2024
-
Ingår i: SCIENCE OF THE TOTAL ENVIRONMENT. - 0048-9697 .- 1879-1026. ; 934
-
Tidskriftsartikel (refereegranskat)abstract
- The expansion of the world 's merchant fleet poses a great threat to the ocean 's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark ( Rhincodon typus ) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation " sites are of significant ecological, socioeconomic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world ( >50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.
|
|
| 16. |
- Andersson, Håkan, et al.
(författare)
-
Simulation of leakage flow through dynamic sealing gaps in hydraulic percussion units using a co-simulation approach
- 2021
-
Ingår i: Simulation (San Diego, Calif.). - : Elsevier B.V.. - 1569-190X .- 1878-1462. ; 111
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, a previously developed co-simulation method has been expanded to also simulate the dynamic behaviour of sealing gap regions in hydraulic percussion units. This approach is based on a 1D system model representing the fluid components and a 3D finite element model representing the structural parts of a hydraulic hammer. The sealing gap is a fundamental feature of a percussion unit, where the reciprocating motion of the piston is generated by the valve mechanism of the sealing gap. When the gap is closed it will prevent fluid flow between regions of different pressure levels. However, a small leakage flow through the gap will always occur which size depends on the clearance and the position of the piston. The method proposed here will take the structural motion and deformation into consideration when calculating the leakage flow. The deformed state of the structure is approximated by a cylindrical surface, in a least square manner, and communicated through the co-simulation interface to the fluid simulation module, and then used when calculating the leakage flow. This method aims at a more accurate simulation of the leakage flow that will not only yield a more realistic description of the mechanism on the local level, but also a more accurate estimation of global parameters such as overall performance and efficiency. The results indicate that the simulated leakage flow will decrease when dynamic gaps are used in comparison to static gaps, which is a consequence of the deformed structure that will generate smaller clearances. The leakage flow for the dynamic gaps will even be lower than for the static perfectly concentric case, mainly due to the reduction of clearances. The results also indicate that the dynamic eccentricity does not have a major influence on the leakage flow. The outcome from this study highlights the potentials of the described co-simulation approach for analysing the dynamics of the sealing gaps in a hydraulic percussion unit (i.e. gap heights, eccentricity ratios, etc.) including the evaluation of leakage flows and its impact on the overall performance. © 2021
|
|
| 17. |
- Appelbom, S, et al.
(författare)
-
The Rapid Implementation of a Psychological Support Model for Frontline Healthcare Workers During the COVID-19 Pandemic: A Case Study and Process Evaluation
- 2021
-
Ingår i: Frontiers in psychiatry. - : Frontiers Media SA. - 1664-0640. ; 12, s. 713251-
-
Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic highlighted the need for psychological support initiatives directed toward frontline healthcare workers, which can be rapidly and sustainably implemented during an infectious disease outbreak. The current case study presents a comprehensive model of psychological support that was implemented at an intensive care unit (ICU) during the first wave of the COVID-19 pandemic. The psychological support model aimed at promoting a resilient stress reaction among frontline staff by protecting physical, social, and psychological resources. The initiatives, targeting different groups of workers, included education and training, peer support, psychologist-supervised and unsupervised group sessions, on-boarding for transferred staff, manager support, and individual sessions for workers experiencing strong stress reactions. The results of the process evaluation of this rapid implementation suggest that peer support initiatives as well as daily group sessions were the most appreciated forms of psychological support. Psychologists involved in organizing and providing the support highlighted several aspects of a successful implementation of the support model: offering support during work hours (preferably after shift), positive attitude of line managers that framed support initiatives as a team effort, and involvement of experienced psychologists able to quickly adjust the content of the support according to the current needs. The study also identified two main problems of the current implementation: the lack of efficient planning due to the use of volunteer work and the need for more structural resources on the organizational level to ensure long-term sustainability of the support model and its implementation among all groups of healthcare staff. The current case study highlights the importance of establishing permanent structural resources and routines for psychological support integrated in clinical practice by healthcare organizations to improve both rapid and sustainable response to future crises.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Chelazzi, D., et al.
(författare)
-
The use of surfactants in the cleaning of works of art
- 2020
-
Ingår i: Current Opinion in Colloid and Interface Science. - : Elsevier BV. - 1359-0294 .- 1879-0399. ; 45, s. 108-123
-
Forskningsöversikt (refereegranskat)abstract
- Surfactants have been historically used for cleaning artifacts, but it was only in the last decades that serendipitous approaches were replaced by research in the field of soft matter and colloid science. Surfactants are components of nanostructured fluids, which were assessed for the removal of soil and aged coatings from paintings and are fundamental in processes that range from the inclusion of grime in micelles to the swelling and dewetting of polymer layers. Intriguing aspects involve the synthesis and use of biodegradable and self-cleavable surfactants, and the confinement of nanostructured fluids in gels, which boost the selectiveness of cleaning interventions. The performances of these advanced systems surpass those of traditional cleaning materials such as solvent blends and thickeners. The most important results are here reviewed and future perspectives given. Besides granting the transfer of cultural heritage to future generations, advanced cleaning materials are relevant to transversal fields, such as detergency, cosmetics, and drug delivery.
|
|
| 23. |
- Gejl, Kasper D., et al.
(författare)
-
Contractile Properties of MHC I and II Fibers From Highly Trained Arm and Leg Muscles of Cross-Country Skiers
- 2021
-
Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about potential differences in contractile properties of muscle fibers of the same type in arms and legs. Accordingly, the present study was designed to compare the force-generating capacity and Ca2+ sensitivity of fibers from arm and leg muscles of highly trained cross-country skiers. Method: Single muscle fibers of m. vastus lateralis and m. triceps brachii of 8 highly trained cross-country skiers were analyzed with respect to maximal Ca2+-activated force, specific force and Ca2+ sensitivity. Result: The maximal Ca2+-activated force was greater for MHC II than MHC I fibers in both the arm (+62 %, P < 0.001) and leg muscle (+77 %, P < 0.001), with no differences between limbs for each MHC isoform. In addition, the specific force of MHC II fibers was higher than that of MHC I fibers in both arms (+41 %, P = 0.002) and legs (+95 %, P < 0.001). The specific force of MHC II fibers was the same in both limbs, whereas MHC I fibers from the m. triceps brachii were, on average, 39% stronger than fibers of the same type from the m. vastus lateralis (P = 0.003). pCa50 was not different between MHC I and II fibers in neither arms nor legs, but the MHC I fibers of m. triceps brachii demonstrated higher Ca2+ sensitivity than fibers of the same type from m. vastus lateralis (P = 0.007). Conclusion: Comparison of muscles in limbs equally well trained revealed that MHC I fibers in the arm muscle exhibited a higher specific force-generating capacity and greater Ca2+ sensitivity than the same type of fiber in the leg, with no such difference in the case of MHC II fibers. These distinct differences in the properties of fibers of the same type in equally well-trained muscles open new perspectives in muscle physiology.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Gerdtsson, Axel, et al.
(författare)
-
Validation of a prediction model for post-chemotherapy fibrosis in nonseminoma patients
- 2023
-
Ingår i: Bju International. - : John Wiley & Sons. - 1464-4096 .- 1464-410X. ; 132:3, s. 329-336
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To validate Vergouwe's prediction model using the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) RETROP database and to define its clinical utility. Materials and methods Vergouwe's prediction model for benign histopathology in post-chemotherapy retroperitoneal lymph node dissection (PCRPLND) uses the following variables: presence of teratoma in orchiectomy specimen; pre-chemotherapy level of alphafetoprotein; b-Human chorionic gonadotropin and lactate dehydrogenase; and lymph node size pre- and postchemotherapy. Our validation cohort consisted of patients included in RETROP, a prospective population-based database of patients in Sweden and Norway with metastatic nonseminoma, who underwent PC-RPLND in the period 2007-2014. Discrimination and calibration analyses were used to validate Vergouwe's prediction model results. Calibration plots were created and a Hosmer-Lemeshow test was calculated. Clinical utility, expressed as opt-out net benefit (NBopt-out), was analysed using decision curve analysis. Results Overall, 284 patients were included in the analysis, of whom 130 (46%) had benign histology after PC-RPLND. Discrimination analysis showed good reproducibility, with an area under the receiver-operating characteristic curve (AUC) of 0.82 (95% confidence interval 0.77-0.87) compared to Vergouwe's prediction model (AUC between 0.77 and 0.84). Calibration was acceptable with no recalibration. Using a prediction threshold of 70% for benign histopathology, NBopt-out was 0.098. Using the model and this threshold, 61 patients would have been spared surgery. However, only 51 of 61 were correctly classified as benign. Conclusions The model was externally validated with good reproducibility. In a clinical setting, the model may identify patients with a high chance of benign histopathology, thereby sparing patients of surgery. However, meticulous follow-up is required.
|
|
| 27. |
- Grinin, V. P., et al.
(författare)
-
Modelling UX Ori star eclipses based on spectral observations with the Nordic Optical Telescope - I. RR Tau
- 2023
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 524:3, s. 4047-4061
-
Tidskriftsartikel (refereegranskat)abstract
- Based on observations obtained with the Nordic Optical Telescope (NOT) we investigate the spectral variability of the Herbig Ae star RR Tau. This star belongs to the UX Ori family, characterized by very deep fadings caused by the screening of the star with opaque fragments (clouds) of the protoplanetary discs. At the moments of such minima one observes strong spectral variability due to the fact that the dust cloud occults, for an observer, not only the star but also a part of the region where the emission spectrum originates. We calculated a series of obscuration models to interpret the observed variability of the H a line parameters. We consider two main obscuration scenarios: (1) the dust screen rises vertically above the circumstellar disc, and (2) the screen intersects the line-of-sight moving azimuthally with the disc. In both cases, the model of the emission region consists of a compact magnetosphere and a magnetocentrifugal disc wind. Comparison with observations shows that the first scenario explains well the variability of the radiation flux, the equivalent width, as well as the asymmetry of the H a line during eclipses, while the second scenario explains them only partly. This permits us to suggest that in the case of RR Tau, the main causes of the eclipses are either a structured disc wind, or the charged dust lifted along the field lines of the poloidal component of the magnetic field of the circumstellar disc.
|
|
| 28. |
|
|
| 29. |
- Holmberg, Carl Jacob, et al.
(författare)
-
The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study
- 2022
-
Ingår i: EUROPEAN JOURNAL OF CANCER. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 40:16
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. Results: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Conclusion: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
- Jensen, R., et al.
(författare)
-
Heterogeneity in subcellular muscle glycogen utilisation during exercise impacts endurance capacity in men
- 2020
-
Ingår i: Journal of Physiology. - 0022-3751 .- 1469-7793. ; 598:19, s. 4271-4292
-
Tidskriftsartikel (refereegranskat)abstract
- Key points: When muscle biopsies first began to be used routinely in research on exercise physiology five decades ago, it soon become clear that the muscle content of glycogen is an important determinant of exercise performance. Glycogen particles are stored in distinct pools within the muscles, but the role of each pool during exercise and how this is affected by diet is unknown. Here, the effects of diet and exercise on these pools, as well as their relation to endurance during prolonged cycling were examined. We demonstrate here that an improved endurance capacity with high carbohydrate loading is associated with a temporal shift in the utilisation of the distinct stores of glycogen pools and is closely linked to the content of the glycogen pool closest to actin and myosin (intramyofibrillar glycogen). These findings highlight the functional importance of distinguishing between different subcellular microcompartments of glycogen in individual muscle fibres. Abstract: In muscle cells, glycogen is stored in three distinct subcellular pools: between or within myofibrils (inter- and intramyofibrillar glycogen, respectively) or beneath the sarcolemma (subsarcolemmal glycogen) and these pools may well have different functions. Here, we investigated the effect of diet and exercise on the content of these distinct pools and their relation to endurance capacity in type 1 and 2 muscle fibres. Following consumption of three different diets (normal, mixed diet = MIX, high in carbohydrate = HIGH, or low in carbohydrate = LOW) for 72 h, 11 men cycled at 75% of (Formula presented.) max until exhaustion. The volumetric content of the glycogen pools in muscle biopsies obtained before, during, and after exercise were quantified by transmission electron micrographs. The mean (SD) time to exhaustion was 150 (30), 112 (22), and 69 (18) minutes in the HIGH, MIX and LOW trials, respectively (P < 0.001). As shown by multiple regression analyses, the intramyofibrillar glycogen content in type 1 fibres, particularly after 60 min of exercise, correlated most strongly with time to exhaustion. In the HIGH trial, intramyofibrillar glycogen was spared during the initial 60 min of exercise, which was associated with levels and utilisation of subsarcolemmal glycogen above normal. In all trials, utilisation of subsarcolemmal and intramyofibrillar glycogen was more pronounced than that of intermyofibrillar glycogen in relative terms. In conclusion, the muscle pool of intramyofibrillar glycogen appears to be the most important for endurance capacity in humans. In addition, a local abundance of subsarcolemmal glycogen reduces the utilisation of intramyofibrillar glycogen during exercise.
|
|
| 38. |
- Karason, Kristjan, 1962, et al.
(författare)
-
Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial
- 2020
-
Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:2, s. 739-50
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Patients with advanced heart failure (AdHF) who are ineligible for heart transplantation (HTx) can become candidates for treatment with a left ventricular assist device (LVAD) in some countries, but not others. This reflects the lack of a systematic analysis of the usefulness of LVAD systems in this context, and of their benefits, limitations and cost-effectiveness. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) study is a Phase IV, prospective, 1:1 randomized, non-blinded, multicentre trial that will examine the impact of assignment to mechanical circulatory support with guideline-directed LVAD destination therapy (GD-LVAD-DT) using the HeartMate 3 (HM3) continuous flow pump vs. guideline-directed medical therapy (GDMT) on survival in a population of AdHF patients ineligible for HTx. Methods A total of 80 patients will be recruited to SweVAD at the seven university hospitals in Sweden. The study population will comprise patients with AdHF (New York Heart Association class IIIB-IV, INTERMACS profile 2-6) who display signs of poor prognosis despite GDMT and who are not considered eligible for HTx. Participants will be followed for 2 years or until death occurs. Other endpoints will be determined by blinded adjudication. Patients who remain on study-assigned interventions beyond 2 years will be asked to continue follow-up for outcomes and adverse events for up to 5 years. Conclusion The SweVAD study will compare survival, medium-term benefits, costs and potential hazards between GD-LVAD-DT and GDMT and will provide a valuable reference point to guide destination therapy strategies for patients with AdHF ineligible for HTx.
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
- Kolman, Krzysztof, 1986, et al.
(författare)
-
pH-Controlled assembly of polyelectrolyte layers on silica nanoparticles in concentrated suspension
- 2022
-
Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 1095-7103 .- 0021-9797. ; 615, s. 265-272
-
Tidskriftsartikel (refereegranskat)abstract
- Hypothesis: Preparation of suspensions of nanoparticles (>1 wt%) coated with a polyelectrolyte multilayers is a challenging task because of the risk of flocculation when a polyelectrolyte is added to a suspension of oppositely charged nanoparticles. This situation can be avoided if the charge density of the polymers and particles is controlled during mixing so as to separate mixing and adsorption events. Experiments: The cationic polyethylenimine (PEI) and the anionic carboxymethylcellulose (CMC) were used as weak polyelectrolytes. Polyelectrolyte multilayers build-up was conducted by reducing the charge of one of the components during the addition of the next component. Charge density was controlled by tuning pH. Analysis of the suspension of coated nanoparticles was done by means of dynamic light scattering, electrophoresis and small angle x-ray scattering measurements, while quartz crystal microbalance was used to study the build-up process on flat silica surfaces. Findings: Charge density, controlled through pH, can be used as a tool to avoid flocculation during layer-by-layer deposition of polyelectrolytes on 20 nm silica particles at high concentration (∼40 wt%). When added to silica at pH 3, PEI did not induce flocculation. Adsorption was triggered by raising the pH to 11, pH at which CMC could be added. The pH was then lowered to 3. The process was repeated, and up to five polyelectrolyte layers were deposited on concentrated silica nanoparticles while inducing minimal aggregation.
|
|
| 42. |
|
|
| 43. |
- Larsen, Filip J, 1977-, et al.
(författare)
-
Mitochondrial oxygen affinity increases after sprint interval training and is related to the improvement in peak oxygen uptake.
- 2020
-
Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 229:3
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The body responds to exercise training by profound adaptations throughout the cardiorespiratory and muscular systems, which may result in improvements in maximal oxygen consumption (VO2 peak) and mitochondrial capacity. By convenience, mitochondrial respiration is often measured at supra-physiological oxygen levels, an approach that ignores any potential regulatory role of mitochondrial affinity for oxygen (p50mito ) at physiological oxygen levels.METHODS: In this study, we examined the p50mito of mitochondria isolated from the Vastus lateralis and Triceps brachii in 12 healthy volunteers before and after a training intervention with 7 sessions of sprint interval training using both leg cycling and arm cranking. The changes in p50mito were compared to changes in whole-body VO2 peak.RESULTS: We here show that p50mito is similar in isolated mitochondria from the Vastus (40 ± 3.8 Pa) compared to Triceps (39 ± 3.3) but decreases (mitochondrial oxygen affinity increases) after 7 sessions of sprint interval training (to 26 ± 2.2 Pa in Vastus and 22 ± 2.7 Pa in Triceps, both p<0.01). The change in VO2 peak modeled from changes in p50mito was correlated to actual measured changes in VO2 peak (R2 =0.41, p=0.002).CONCLUSION: Together with mitochondrial respiratory capacity, p50mito is a critical factor when measuring mitochondrial function, it can decrease with sprint interval training and should be considered in the integrative analysis of the oxygen cascade from lung to mitochondria.
|
|
| 44. |
- Mainwaring, Oliver, et al.
(författare)
-
ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
|
|
| 45. |
|
|
| 46. |
- Nilsson, Magnus, et al.
(författare)
-
Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
- 2022
-
Ingår i: Drug Design, Development and Therapy. - : Informa Healthcare. - 1177-8881. ; 16, s. 2901-2917
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 mu g/kg and AZD4604 at 30 mu g/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
- Russell, B., et al.
(författare)
-
Risk of bladder cancer death in patients younger than 50 with non-muscle-invasive and muscle-invasive bladder cancer
- 2022
-
Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:1, s. 27-33
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction and objectives Bladder cancer is primarily a disease of older age and little is known about the differences between patients diagnosed with bladder cancer at a younger versus older age. Our objectives were to compare bladder cancer specific survival in patients aged Materials and methods The Swedish bladder cancer database provided data on patient demographics, clinical characteristics and treatments for this observational study. Cox proportional hazard regression models were adjusted for appropriate variables. All analyses were stratified by disease stage (non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. Furthermore, we compared the frequency of lower urinary tract infections within 24 months prior to bladder cancer diagnosis by sex and age groups. Results The study included 15,452 newly-diagnosed BC patients (1997-2014); 1,207 (8%) patients were <50 whilst 14,245 (92%) were aged 50-70. Patients aged <50 at diagnosis were at a decreased risk of bladder cancer death (HR = 0.82, 95%CI: 0.68-0.99) compared to those aged 50-70. When stratified by non-muscle-invasive and muscle-invasive bladder cancer, this association remained in non-muscle-invasive patients only (<50, HR = 0.43, 95% CI: 0.28-0.64). The frequency of lower urinary tract infection diagnoses did not differ between younger and older patients in either men or women. Conclusions Patients diagnosed with non-muscle-invasive bladder cancer when aged <50 are at decreased risk of bladder cancer-specific death when compared to their older (50-70) counterparts. These observations raise relevant research questions about age-related differences in diagnostic procedures, clinical decision-making and, not least, potential differences in tumour biology.
|
|
| 50. |
|
|
