| 1. |
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| 2. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 6. |
- Khatri, C, et al.
(författare)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Tidskriftsartikel (refereegranskat)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 7. |
- Stroth, U., et al.
(författare)
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Progress from ASDEX Upgrade experiments in preparing the physics basis of ITER operation and DEMO scenario development
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L-H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced D α H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts.
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| 8. |
- Reimerdes, H., et al.
(författare)
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Overview of the TCV tokamak experimental programme
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- The tokamak a configuration variable (TCV) continues to leverage its unique shaping capabilities, flexible heating systems and modern control system to address critical issues in preparation for ITER and a fusion power plant. For the 2019-20 campaign its configurational flexibility has been enhanced with the installation of removable divertor gas baffles, its diagnostic capabilities with an extensive set of upgrades and its heating systems with new dual frequency gyrotrons. The gas baffles reduce coupling between the divertor and the main chamber and allow for detailed investigations on the role of fuelling in general and, together with upgraded boundary diagnostics, test divertor and edge models in particular. The increased heating capabilities broaden the operational regime to include T (e)/T (i) similar to 1 and have stimulated refocussing studies from L-mode to H-mode across a range of research topics. ITER baseline parameters were reached in type-I ELMy H-modes and alternative regimes with 'small' (or no) ELMs explored. Most prominently, negative triangularity was investigated in detail and confirmed as an attractive scenario with H-mode level core confinement but an L-mode edge. Emphasis was also placed on control, where an increased number of observers, actuators and control solutions became available and are now integrated into a generic control framework as will be needed in future devices. The quantity and quality of results of the 2019-20 TCV campaign are a testament to its successful integration within the European research effort alongside a vibrant domestic programme and international collaborations.
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| 9. |
- Sugai, H., et al.
(författare)
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Updated Design of the CMB Polarization Experiment Satellite LiteBIRD
- 2020
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Ingår i: Journal of Low Temperature Physics. - : Springer Science and Business Media LLC. - 0022-2291 .- 1573-7357. ; 199:3-4, s. 1107-1117
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Tidskriftsartikel (refereegranskat)abstract
- Recent developments of transition-edge sensors (TESs), based on extensive experience in ground-based experiments, have been making the sensor techniques mature enough for their application on future satellite cosmic microwave background (CMB) polarization experiments. LiteBIRD is in the most advanced phase among such future satellites, targeting its launch in Japanese Fiscal Year 2027 (2027FY) with JAXA's H3 rocket. It will accommodate more than 4000 TESs in focal planes of reflective low-frequency and refractive medium-and-high-frequency telescopes in order to detect a signature imprinted on the CMB by the primordial gravitational waves predicted in cosmic inflation. The total wide frequency coverage between 34 and 448 GHz enables us to extract such weak spiral polarization patterns through the precise subtraction of our Galaxy's foreground emission by using spectral differences among CMB and foreground signals. Telescopes are cooled down to 5 K for suppressing thermal noise and contain polarization modulators with transmissive half-wave plates at individual apertures for separating sky polarization signals from artificial polarization and for mitigating from instrumental 1/f noise. Passive cooling by using V-grooves supports active cooling with mechanical coolers as well as adiabatic demagnetization refrigerators. Sky observations from the second Sun-Earth Lagrangian point, L2, are planned for 3 years. An international collaboration between Japan, the USA, Canada, and Europe is sharing various roles. In May 2019, the Institute of Space and Astronautical Science, JAXA, selected LiteBIRD as the strategic large mission No. 2.
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| 10. |
- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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| 11. |
- Meagher, N. S., et al.
(författare)
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Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
- 2022
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 28:24, s. 5383-5395
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primaryMOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and geneexpression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors ( MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio ( HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
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| 12. |
- Aprile, E., et al.
(författare)
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Emission of single and few electrons in XENON1T and limits on light dark matter
- 2022
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 106:2
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Tidskriftsartikel (refereegranskat)abstract
- Delayed single- and few-electron emissions plague dual-phase time projection chambers, limiting their potential to search for light-mass dark matter. This paper examines the origins of these events in the XENON1T experiment. Characterization of the intensity of delayed electron backgrounds shows that the resulting emissions are correlated, in time and position, with high-energy events and can effectively be vetoed. In this work we extend previous S2-only analyses down to a single electron. From this analysis, after removing the correlated backgrounds, we observe rates <30 events/(electron×kg×day) in the region of interest spanning 1 to 5 electrons. We derive 90% confidence upper limits for dark matter-electron scattering, first direct limits on the electric dipole, magnetic dipole, and anapole interactions, and bosonic dark matter models, where we exclude new parameter space for dark photons and solar dark photons.
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| 13. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 14. |
- Seidel, J. V., et al.
(författare)
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Hot Exoplanet Atmospheres Resolved with Transit Spectroscopy (HEARTS) : V. Detection of sodium on the bloated super-Neptune WASP-166b
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 641
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Tidskriftsartikel (refereegranskat)abstract
- Planet formation processes or evolution mechanisms are surmised to be at the origin of the hot Neptune desert. Studying exoplanets currently living within or at the edge of this desert could allow disentangling the respective roles of formation and evolution. We present the High Accuracy Radial velocity Planet Searcher (HARPS) transmission spectrum of the bloated super-Neptune WASP-166b, located at the outer rim of the Neptune desert. Neutral sodium is detected at the 3.4σ level (0.455†±â€ 0.135%), with a tentative indication of line broadening, which could be caused by winds blowing sodium farther into space, a possible manifestation of the bloated character of these highly irradiated worlds. We put this detection into context with previous work claiming a non-detection of sodium in the same observations and show that the high noise in the trace of the discarded stellar sodium lines was responsible for the non-detection. We highlight the impact of this low signal-to-noise ratio remnant on detections for exoplanets similar to WASP-166b.
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| 15. |
- Farnocchia, Davide, et al.
(författare)
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The Second International Asteroid Warning Network Timing Campaign: 2005 LW3
- 2023
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Ingår i: The Planetary Science Journal. - : Institute of Physics (IOP). - 2632-3338. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- The Earth close approach of near-Earth asteroid 2005 LW3 on 2022 November 23 represented a good opportunity for a second observing campaign to test the timing accuracy of astrometric observation. With 82 participating stations, the International Asteroid Warning Network collected 1046 observations of 2005 LW3 around the time of the close approach. Compared to the previous timing campaign targeting 2019 XS, some individual observers were able to significantly improve the accuracy of their reported observation times. In particular, U.S. surveys achieved good timing performance. However, no broad, systematic improvement was achieved compared to the previous campaign, with an overall negative bias persisting among the different observers. The calibration of observing times and the mitigation of timing errors should be important future considerations for observers and orbit computers, respectively.
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| 16. |
- Heinze, Karolin, et al.
(författare)
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Validated biomarker assays confirm ARID1A loss is confounded with MMR deficiency, CD8 TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.
- 2021
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Ingår i: The Journal of pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 256:4, s. 388-401
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Tidskriftsartikel (refereegranskat)abstract
- ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1,623 endometriosis-associated ovarian carcinomas, including 1,078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p<0.001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.035, versus single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. This article is protected by copyright. All rights reserved.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Schwartz, K. L., et al.
(författare)
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Best practice guidance for antibiotic audit and feedback interventions in primary care: a modified Delphi study from the Joint Programming Initiative on Antimicrobial resistance: Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN)
- 2023
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Ingår i: Antimicrobial Resistance and Infection Control. - 2047-2994. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrimary care is a critical partner for antimicrobial stewardship efforts given its high human antibiotic usage. Peer comparison audit and feedback (A & F) is often used to reduce inappropriate antibiotic prescribing. The design and implementation of A & F may impact its effectiveness. There are no best practice guidelines for peer comparison A & F in antibiotic prescribing in primary care.ObjectiveTo develop best practice guidelines for peer comparison A & F for antibiotic prescribing in primary care in high income countries by leveraging international expertise via the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network.MethodsWe used a modified Delphi process to achieve convergence of expert opinions on best practice statements for peer comparison A & F based on existing evidence and theory. Three rounds were performed, each with online surveys and virtual meetings to enable discussion and rating of each best practice statement. A five-point Likert scale was used to rate consensus with a median threshold score of 4 to indicate a consensus statement.ResultsThe final set of guidelines include 13 best practice statements in four categories: general considerations (n = 3), selecting feedback recipients (n = 1), data and indicator selection (n = 4), and feedback delivery (n = 5).ConclusionWe report an expert-derived best practice recommendations for designing and evaluating peer comparison A & F for antibiotic prescribing in primary care. These 13 statements can be used by A & F designers to optimize the impact of their quality improvement interventions, and improve antibiotic prescribing in primary care.
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| 21. |
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| 22. |
- Bychkov, D, et al.
(författare)
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Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 4037-
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Tidskriftsartikel (refereegranskat)abstract
- The treatment of patients with ERBB2 (HER2)-positive breast cancer with anti-ERBB2 therapy is based on the detection of ERBB2 gene amplification or protein overexpression. Machine learning (ML) algorithms can predict the amplification of ERBB2 based on tumor morphological features, but it is not known whether ML-derived features can predict survival and efficacy of anti-ERBB2 treatment. In this study, we trained a deep learning model with digital images of hematoxylin–eosin (H&E)-stained formalin-fixed primary breast tumor tissue sections, weakly supervised by ERBB2 gene amplification status. The gene amplification was determined by chromogenic in situ hybridization (CISH). The training data comprised digitized tissue microarray (TMA) samples from 1,047 patients. The correlation between the deep learning–predicted ERBB2 status, which we call H&E-ERBB2 score, and distant disease-free survival (DDFS) was investigated on a fully independent test set, which included whole-slide tumor images from 712 patients with trastuzumab treatment status available. The area under the receiver operating characteristic curve (AUC) in predicting gene amplification in the test sets was 0.70 (95% CI, 0.63–0.77) on 354 TMA samples and 0.67 (95% CI, 0.62–0.71) on 712 whole-slide images. Among patients with ERBB2-positive cancer treated with trastuzumab, those with a higher than the median morphology–based H&E-ERBB2 score derived from machine learning had more favorable DDFS than those with a lower score (hazard ratio [HR] 0.37; 95% CI, 0.15–0.93; P = 0.034). A high H&E-ERBB2 score was associated with unfavorable survival in patients with ERBB2-negative cancer as determined by CISH. ERBB2-associated morphology correlated with the efficacy of adjuvant anti-ERBB2 treatment and can contribute to treatment-predictive information in breast cancer.
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| 23. |
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| 24. |
- Bäckström, David C, M.D. 1978-, et al.
(författare)
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NfL as a biomarker for neurodegeneration and survival in Parkinson disease
- 2020
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Ingår i: Neurology. - : Wolters Kluwer. - 0028-3878 .- 1526-632X. ; 95:7, s. e827-e838
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).METHODS: We investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.RESULTS: Higher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.CONCLUSIONS: cNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.
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| 25. |
- Colombo, Diego, et al.
(författare)
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Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells
- 2022
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Ingår i: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models. The caffeic acid phenethyl ester (CAPE), inhibited ubiquitin-specific protease 8 (USP8), but not proteasomal DUBs in cell-free assays. When CAPE was combined with cisplatin in nine cell lines representative of various histotypes a synergistic effect was observed in TOV112D cells and in the cisplatin-resistant IGROV-1/Pt1 variant, both of endometrioid type and carrying mutant TP53. In the latter cells, persistent G1 accumulation upon combined treatment associated with p27(kip1) protein levels was observed. The synergy was not dependent on apoptosis induction, and appeared to occur in cells with higher USP8 levels. In vivo antitumor activity studies supported the advantage of the combination of CAPE and cisplatin in the subcutaneous model of cisplatin-resistant IGROV-1/Pt1 ovarian carcinoma as well as CAPE activity on intraperitoneal disease. This study reveals the therapeutic potential of CAPE in cisplatin-resistant ovarian tumors as well as in tumors expressing USP8.
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| 26. |
- Corno, Cristina, et al.
(författare)
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The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis
- 2022
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Ingår i: Frontiers in Cell and Developmental Biology. - : FRONTIERS MEDIA SA. - 2296-634X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The identification of therapeutic approaches to improve response to platinum-based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a large family of ubiquitin proteases implicated in a variety of cellular functions and may contribute to tumor aggressive features through regulation of processes such as proliferation and cell death. Among the subfamily of ubiquitin-specific peptidases, USP8 appears to be involved in modulation of cancer cell survival by still poorly understood mechanisms. Thus, we used ovarian carcinoma cells of different histotypes, including cisplatin-resistant variants with increased survival features to evaluate the efficacy of molecular targeting of USP8 as a strategy to overcome drug resistance/modulate cisplatin response. We performed biochemical analysis of USP8 activity in pairs of cisplatin-sensitive and -resistant cells and found increased USP8 activity in resistant cells. Silencing of USP8 resulted in decreased activation of receptor tyrosine kinases and increased sensitivity to cisplatin in IGROV-1/Pt1 resistant cells as shown by colony forming assay. Increased cisplatin sensitivity was associated with enhanced cisplatin-induced caspase 3/7 activation and apoptosis, a phenotype also observed in cisplatin sensitive cells. Increased apoptosis was linked to FLIPL decrease and cisplatin induction of caspase 3 in IGROV-1/Pt1 cells, cisplatin-induced claspin and survivin down-regulation in IGROV-1 cells, thereby showing a decrease of anti-apoptotic proteins. Immunohistochemical staining on 65 clinical specimens from advanced stage ovarian carcinoma indicated that 40% of tumors were USP8 positive suggesting that USP8 is an independent prognostic factor for adverse outcome when considering progression free survival as a clinical end-point. Taken together, our results support that USP8 may be of diagnostic value and may provide a therapeutic target to improve the efficacy of platinum-based therapy in ovarian carcinoma.
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| 27. |
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| 28. |
- de Melo, A. L. L., et al.
(författare)
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Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma
- 2022
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 61:11, s. 1425-1433
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Tidskriftsartikel (refereegranskat)abstract
- Background Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously. Materials and methods A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses. Results Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma. Conclusion LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.
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| 29. |
- Forsvall, Andreas, et al.
(författare)
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Prostate biopsy quality and patient experience with the novel Forsvall biopsy needle - a randomized controlled non-inferiority trial
- 2021
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 55:3, s. 235-241
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Tidskriftsartikel (refereegranskat)abstract
- Background Transrectal prostate biopsy (TRbx) carries an increasing risk of infection. The Forsvall Needle Prototype (FNP) is a novel biopsy needle that reduces bacterial load brought across the rectum and may therefore reduce infection risk. The objective of this study was to compare biopsy length, quality and patient experience for the FNP Version 2 (FNP2) versus a standard Tru-Cut needle. Methods We conducted a randomized, parallel-group, non-inferiority trial with twenty consecutive patients eligible for TRbx. Participants were randomized to undergo TRbx using either FNP2 or a standard Tru-Cut needle. The primary outcome was difference in mean biopsy lengths measured by the pathologist. FNP2 biopsy lengths <= 1.35 mm of the standard needle length were considered non-inferior. Secondary outcomes were biopsy length in the needle chamber and immediately after removal, biopsy quality, biopsy fragmentation, patient discomfort/pain, and complications (immediate and after 14 and 30 days). Results Mean pathologist-measured FNP2 biopsy length was non-inferior compared to the standard Tru-Cut needle (0.02 mm longer, 95%CI-0.73 to 0.76 mm). Biopsy length in the needle chamber and immediately after removal were also non-inferior. Biopsy quality and patient discomfort were not significantly different for the FNP2 and the standard Tru-Cut needle. Biopsy fragmentation was more common in the FNP2 group. Conclusions The FNP2 biopsy needle is non-inferior to the Tru-Cut needle in terms of biopsy length and not significantly different in terms of biopsy quality and patient experience. Future studies will evaluate the Forsvall needle design's effect on post-biopsy infection risk.
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| 30. |
- Glaser, N, et al.
(författare)
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Transcatheter aortic valve replacement using the iSleeve expandable sheath in small femoral arteries
- 2021
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Ingår i: Open heart. - : BMJ. - 2053-3624. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Small femoral arteries have been associated with a higher risk of vascular complications in transfemoral transcatheter aortic valve replacement (TAVR). We investigated the feasibility and safety of TAVR in patients with small femoral arteries.MethodsIn this observational study, we included 82 patients who underwent transfemoral TAVR with the ACURATE neo system using the expandable 14F iSleeve sheath between 2018 and 2019 at Karolinska University Hospital, Sweden. Of these, 41 patients had a minimal femoral artery diameter of ≥5.5 mm (mean 6.5, range 5.5–9.2), and 41 patients had a minimal femoral artery diameter <5.5 mm (mean 4.9, range 3.9–5.4).ResultsThere was no significant difference in major vascular and bleeding complications between the small femoral artery group (7%) and the normal femoral artery group (2%) (p=0.62). The total of major and minor vascular complications did not differ significantly according to femoral artery size (17% vs 5%) (p=0.16). The iSleeve sheath was not correlated with any of the complications. The use of the iSleeve sheath was unsuccessful in four patients (5%), of which one patient had a small femoral artery diameter.ConclusionTransfemoral TAVR with the ACURATE neo system using the iSleeve sheath is a promising method for patients with small femoral arteries even though we found a trend towards higher rates of complications in these patients. The use of expandable sheaths may expand the spectrum of patients that can be treated with transfemoral TAVR, and thus may improve the prognosis in patients with severe aortic valve stenosis.
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| 31. |
- Gubat, Johannes, 1986-, et al.
(författare)
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Comprehensive Target Screening and Cellular Profiling of the Cancer-Active Compound b-AP15 Indicate Abrogation of Protein Homeostasis and Organelle Dysfunction as the Primary Mechanism of Action
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Dienone compounds have been demonstrated to display tumor-selective anti-cancer activity independently of the mutational status of TP53. Previous studies have shown that cell death elicited by this class of compounds is associated with inhibition of the ubiquitin-proteasome system (UPS). Here we extend previous findings by showing that the dienone compound b-AP15 inhibits proteasomal degradation of long-lived proteins. We show that exposure to b-AP15 results in increased association of the chaperones VCP/p97/Cdc48 and BAG6 with proteasomes. Comparisons between the gene expression profile generated by b-AP15 to those elicited by siRNA showed that knock-down of the proteasome-associated deubiquitinase (DUB) USP14 is the closest related to drug response. USP14 is a validated target for b-AP15 and we show that b-AP15 binds covalently to two cysteines, Cys203 and Cys257, in the ubiquitin-binding pocket of the enzyme. Consistent with this, deletion of USP14 resulted in decreased sensitivity to b-AP15. Targeting of USP14 was, however, found to not fully account for the observed proteasome inhibition. In search for additional targets, we utilized genome-wide CRISPR/Cas9 library screening and Proteome Integral Solubility Alteration (PISA) to identify mechanistically essential genes and b-AP15 interacting proteins respectively. Deletion of genes encoding mitochondrial proteins decreased the sensitivity to b-AP15, suggesting that mitochondrial dysfunction is coupled to cell death induced by b-AP15. Enzymes known to be involved in Phase II detoxification such as aldo-ketoreductases and glutathione-S-transferases were identified as b-AP15-targets using PISA. The finding that different exploratory approaches yielded different results may be explained in terms of a “target” not necessarily connected to the “mechanism of action” thus highlighting the importance of a holistic approach in the identification of drug targets. We conclude that b-AP15, and likely also other dienone compounds of the same class, affect protein degradation and proteasome function at more than one level.
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| 32. |
- Gubat, Johannes, 1986-
(författare)
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Identifying Essential Deubiquitinase Interactions and Targeting Protein Ubiquitination in Cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is the second leading cause of death globally and is one of the most pressing health issues today. While significant advances have been made in cancer treatment, drug resistance and toxicity remain formidable obstacles to successful therapy. Thus, there is a need to find novel targets that pave the way for new cancer therapeutics. Ubiquitination, the process of tagging substrate proteins with ubiquitin molecules, regulates many of the pathways that underlie cancer progression. This thesis aims to explore innovative strategies for combating cancer by focusing on crucial elements within the ubiquitination machinery, specifically the Ubiquitin-Proteasome System (UPS) and deubiquitinases (DUBs). In Paper I, we employed the Connectivity Map to discern UPS inhibitors by analyzing the gene expression patterns of various compounds in comparison to those induced by proteasome perturbation. In Paper II, we employed orthogonal methods to identify the primary mechanism for the cytotoxicity of b-AP15. Here, we showed that pharmacologic doses of b-AP15 resulted in strong proteasome inhibition and that cytotoxicity is mediated through the mitochondria and influenced by the proteasome-associated DUB, USP14. In Paper III, we explored the role of USP14 in colorectal cancer cells and evaluated its potential as a cancer target. We found that the genetic deletion of USP14 confers a quiescent phenotype to cancer cells. In Paper IV, we used CRISPR-based screens to search for new deubiquitinase targets. We identified deubiquitinase interactions essential for cancer and explored the possibility of combinatorial deubiquitinase targeting. We pinpointed highly-networked deubiquitinases (PSMD14, USP9X, USP39, and USP7) and deubiquitinase pairs represent promising drug targets. This thesis underscores the importance of the ubiquitination process in the search for novel cancer therapeutics and provides new avenues to explore in developing therapies based on the inhibition of deubiquitinases.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Jarrett, Benjamin J.M., et al.
(författare)
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Experimental adaptation of native parasitoids to the invasive insect pest, Drosophila suzukii
- 2022
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Ingår i: Biological Control. - : Elsevier BV. - 1049-9644. ; 167
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Tidskriftsartikel (refereegranskat)abstract
- The spread of invasive pests is increasing due to greater global transportation and climate change-mediated range shifts. In a new community, these invasive species provide a novel resource that native predators or parasitoids can evolve to utilise. For invasive agricultural pests, this could provide top-down control; however, initial attack rates on invasive species in the wild are generally low. The potential for rapid adaptive evolution of native species to improve developmental success on invasive species is unknown. We address this by focusing on Drosophila suzukii, a polyphagous invasive pest, and two cosmopolitan Drosophila parasitoids found in North America prior to the arrival of D. suzukii (Pachycrepoideus vindemiae and Trichopria drosophilae). We experimentally evolved three replicate populations of both species on D. suzukii and the cosmopolitan D. melanogaster, a common host for both parasitoids. We found evidence that P. vindemiae increased developmental success by 88% (95% credible intervals = [−14%, 254%]) and T. drosophilae increased developmental success by 259% [38%, 711%] on D. suzukii after only three generations of selection, despite very low founding sizes of 2 and 30 wasps, respectively. These results demonstrate that rapid evolution of increased virulence is possible even from low genetic diversity, with implications for integrating evolutionary techniques into biological control of invasive species.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Linder, Adam, et al.
(författare)
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The specific organism : Not bacterial gram type: Drives the inflammatory response in septic shock
- 2020
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 12:2, s. 182-190
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Tidskriftsartikel (refereegranskat)abstract
- Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns.
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| 42. |
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| 43. |
- Misery, L., et al.
(författare)
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Pathophysiology and management of sensitive skin : position paper from the special interest group on sensitive skin of the International Forum for the Study of Itch (IFSI)
- 2020
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Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959 .- 1468-3083. ; 34:2, s. 222-229
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Tidskriftsartikel (refereegranskat)abstract
- The special interest group on sensitive skin of the International Forum for the Study of Itch previously defined sensitive skin as a syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus and tingling sensations) in response to stimuli that normally should not provoke such sensations. This additional paper focuses on the pathophysiology and the management of sensitive skin. Sensitive skin is not an immunological disorder but is related to alterations of the skin nervous system. Skin barrier abnormalities are frequently associated, but there is no cause and direct relationship. Further studies are needed to better understand the pathophysiology of sensitive skin – as well as the inducing factors. Avoidance of possible triggering factors and the use of well-tolerated cosmetics, especially those containing inhibitors of unpleasant sensations, might be suggested for patients with sensitive skin. The role of psychosocial factors, such as stress or negative expectations, might be relevant for subgroups of patients. To date, there is no clinical trial supporting the use of topical or systemic drugs in sensitive skin. The published data are not sufficient to reach a consensus on sensitive skin management. In general, patients with sensitive skin require a personalized approach, taking into account various biomedical, neural and psychosocial factors affecting sensitive skin.
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| 44. |
- Mofers, Arjan, et al.
(författare)
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Identification of proteasome inhibitors using analysis of gene expression profiles
- 2020
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Ingår i: European Journal of Pharmacology. - : ELSEVIER. - 0014-2999 .- 1879-0712. ; 889
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of the 20S proteasome such as bortezomib (Velcade((R))) and carfilzomib (Kypriolis((R))) are in clinical use for the treatment of patients with multiple myeloma and mantle cell lymphoma. In an attempt to identify novel inhibitors of the ubiquitin-proteasome system (UPS) we used the connectivity map (CMap) resource, based on alterations of gene expression profiles by perturbagens, and performed COMPARE analyses of drug sensitivity patterns in the NCI60 panel. Cmap analysis identified a large number of small molecules with strong connectivity to proteasome inhibition, including both well characterized inhibitors of the 20S proteasome and molecules previously not described to inhibit the UPS. A number of these compounds have been reported to be cytotoxic to tumor cells and were tested for their ability to decrease processing of proteasome substrates. The antibiotic thiostrepton and the natural products celastrol and curcumin induced strong accumulation of polyubiquitinated proteasome substrates in exposed cells. Other compounds elicited modest increases of proteasome substrates, including the protein phosphatase inhibitor BCI-Cl and the farnesyltransferase inhibitor manumycin A, suggesting that these compounds inhibit proteasome function. Induction of chaperone expression in the absence of proteasome inhibition was observed by a number of compounds, suggesting other effects on the UPS. We conclude that the combination of bioinformatic analyses and cellular assays resulted in the identification of compounds with potential to inhibit the UPS.
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| 45. |
- Mofers, Arjan, 1990-
(författare)
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Proteasome Inhibitors against Cancer: Determining Biology and Finding Novel Compounds
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer continues to be a tremendous burden on society in terms of loss of quality of life and life-years. The ubiquitin proteasome system (UPS), responsible for the bulk of protein turnover in the cell, is considered an attractive target in cancer therapy. The proteolytic subunit of the UPS, the 20S, is targeted by three clinically approved anti-cancer drugs: Bortezomib, Carfilzomib, and Ixazomib. Proteins destined for degradation by the UPS are tagged with small protein ubiquitin. The 19S regulatory cap is responsible for recognition and processing of these ubiquitinated substrates, followed by proteolysis by the 20S. Deubiquitination by proteolytic enzymes of the 19S is an essential step in the progression of substrates to progress into the 20S. Our strategy is to pharmacologically inhibit the deubiquitinating enzymes associated with the 19S with the goal of disrupting the degradation of substrates. In Paper I of this thesis, we explore the occurrence of resistance to the 19S deubiquitinating enzyme inhibitor b-AP15. We find that minimal resistance to this compound occurs, and the small observed induction of resistance is likely mediated by glutathione. We also find that cells that are slow- or non-cycling are particularly insensitive to the treatment. In Paper II we employ screening methods based on the chemical properties of b-AP15 and find that a small subset of the screened compounds are relatively selective UPS inhibitors. In Paper III we employ a different screening methods, based on the gene expression profiles associated with disruption of the UPS. This screen finds several compounds with previously described UPS inhibitory effects but also compounds with different proposed mechanisms of action. In both Paper II and Paper III we reflect on the chemical structure of the compounds and challenges that come with chemical groups that are potentially promiscuously reactive. In Paper IV we explore the validity of b-AP15 as a treatment for acute lymphoblastic leukemia, a form of cancer for which the efficacy of b-AP15 has not been fully elucidated. This thesis contributes to the body of work supporting 19S inhibition in general, and 19S inhibition with b-AP15 in particular, as a promising modality for the treatment of cancer.
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| 46. |
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| 47. |
- Pellegrini, Paola, 1986-, et al.
(författare)
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Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:13
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib.
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| 48. |
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| 49. |
- Selvaraju, Karthik, et al.
(författare)
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Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System
- 2021
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.
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| 50. |
- Steigen, T, et al.
(författare)
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Age-Stratified Outcome in Treatment of Left Main Coronary Artery Stenosis: A NOBLE Trial Substudy
- 2021
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Ingår i: Cardiology. - : S. Karger AG. - 1421-9751 .- 0008-6312. ; 146:4, s. 409-418
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> In the treatment of left main coronary artery (LMCA) disease, patients’ age may affect the clinical outcome after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This study stratified the clinical outcome according to the age of patients treated for LMCA stenosis with PCI or CABG in the Nordic-Baltic-British Left Main Revascularization (NOBLE) study. <b><i>Methods:</i></b> Patients with LMCA disease were enrolled in 36 centers in northern Europe and randomized 1:1 to treatment by PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST elevation myocardial infarction. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCEs), a composite of all-cause mortality, nonprocedural myocardial infarction, any repeat coronary revascularization, and stroke. Age-stratified analysis was performed for the groups younger and older than 67 years and for patients older than 80 years. <b><i>Results:</i></b> For patients ≥67 years, the 5-year MACCEs were 35.7 versus 22.3% (hazard ratio [HR] 1.72 [95% confidence interval [CI] 1.27–2.33], <i>p</i> = 0.0004) for PCI versus CABG. The difference in MACCEs was driven by more myocardial infarctions (10.8 vs. 3.8% HR 3.01 [95% CI 1.52–5.96], <i>p</i> = 0.0009) and more repeat revascularizations (19.5 vs. 10.0% HR 2.01 [95% CI 1.29–3.12], <i>p</i> = 0.002). In patients younger than 67 years, MACCE was 20.5 versus 15.3% (HR 1.38 [95% CI 0.93–2.06], <i>p</i> = 0.11 for PCI versus CABG. All-cause mortality was similar after PCI and CABG in both age-groups. On multivariate analysis, age was a predictor of MACCE, along with PCI, diabetes, and SYNTAX score. <b><i>Conclusions:</i></b> As the overall NOBLE results show revascularization of LMCA disease, age of 67 years or older was associated with lower 5-year MACCE after CABG compared to PCI. Clinical outcomes were not significantly different in the subgroup younger than 67 years, although no significant interaction was present between age and treatment. Mortality was similar for all subgroups (ClinicalTrials.gov identifier: NCT01496651).
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