| 1. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
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| 3. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 4. |
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| 5. |
- Coppejans, D. L., et al.
(författare)
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A Mildly Relativistic Outflow from the Energetic, Fast-rising Blue Optical Transient CSS161010 in a Dwarf Galaxy
- 2020
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 895:1
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Tidskriftsartikel (refereegranskat)abstract
- We present X-ray and radio observations of the Fast Blue Optical Transient CRTS-CSS161010 J045834-081803 (CSS161010 hereafter) at t = 69-531 days. CSS161010 shows luminous X-ray (L-x similar to 5 x 10(39) erg s(-1)) and radio (L-nu similar to 10(29) erg s(-1) Hz(-1)) emission. The radio emission peaked at similar to 100 days post-transient explosion and rapidly decayed. We interpret these observations in the context of synchrotron emission from an expanding blast wave. CSS161010 launched a mildly relativistic outflow with velocity Gamma beta c >= 0.55c at similar to 100 days. This is faster than the non-relativistic AT 2018cow (Gamma beta c similar to 0.1c) and closer to ZTF18abvkwla (Gamma beta c >= 0.3c at 63 days). The inferred initial kinetic energy of CSS161010 (E-k greater than or similar to 10(51) erg) is comparable to that of long gamma-ray bursts, but the ejecta mass that is coupled to the mildly relativistic outflow is significantly larger (similar to 0.01-.1 M-circle dot). This is consistent with the lack of observed gamma-rays. The luminous X-rays were produced by a different emission component to the synchrotron radio emission. CSS161010 is located at similar to 150 Mpc in a dwarf galaxy with stellar mass M-* similar to 10(7) M-circle dot and specific star formation rate sSFR similar to 0.3 Gyr(-1). This mass is among the lowest inferred for host galaxies of explosive transients from massive stars. Our observations of CSS161010 are consistent with an engine-driven aspherical explosion from a rare evolutionary path of a H-rich stellar progenitor, but we cannot rule out a stellar tidal disruption event on a centrally located intermediate-mass black hole. Regardless of the physical mechanism, CSS161010 establishes the existence of a new class of rare (rate < 0.4% of the local core-collapse supernova rate) H-rich transients that can launch mildly relativistic outflows.
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| 6. |
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| 7. |
- Elg, Alf Peter, et al.
(författare)
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Research project EMPIR 19ENG02 future energy
- 2020
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Ingår i: VDE High Voltage Technology 2020. - : VDE Verlag GmbH. - 9783800753550 ; , s. 252-257
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Konferensbidrag (refereegranskat)abstract
- Society's increasing demand for electrical energy, along with the increased integration of remote renewable generation has driven transmission levels to ever higher voltages in order to maintain (or improve) grid efficiency. Consequently, high voltage testing and monitoring beyond voltage levels covered by presently available metrology infrastructures are needed to secure availability and quality of supply. Calibration services for Ultra-High Voltage Direct Current (UHVDC) presently are only available up to 1000 kV. There is a need to extend the DC calibration capabilities for voltage instrument transformers up to 1200 kV and for factory component testing capabilities up to 2000 kV. Also, methods for linear extension of lightning impulse calibration, for dielectric testing of UHV grid equipment, urgently need revision. Recent research has raised questions regarding the validity of the current linearity extension methods for voltages beyond 2500 kV. Furthermore, new methods for calibration are needed for the 0.2 class HVAC voltage instrument transformers for system voltages up to 1200 kV. The current methods used for determination of the voltage dependence are very time consuming, raising the need for methods allowing faster assessment. Finally, with new HVDC transmission grids and associated components, novel methods are needed for detection, classification and localisation of partial discharge (PD) under DC stress. The industry needs methods for reliable monitoring of critical components such as cables, for both HVAC and HVDC, and gas insulated substations (GIS), and techniques for addressing new challenges introduced by HVDC technologies, such as the ability to distinguish PD signals from switching transients in converters and other sources of noise.
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| 8. |
- Pelisek, J, et al.
(författare)
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Biobanking: Objectives, Requirements, and Future Challenges-Experiences from the Munich Vascular Biobank
- 2019
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Collecting biological tissue samples in a biobank grants a unique opportunity to validate diagnostic and therapeutic strategies for translational and clinical research. In the present work, we provide our long-standing experience in establishing and maintaining a biobank of vascular tissue samples, including the evaluation of tissue quality, especially in formalin-fixed paraffin-embedded specimens (FFPE). Our Munich Vascular Biobank includes, thus far, vascular biomaterial from patients with high-grade carotid artery stenosis (n = 1567), peripheral arterial disease (n = 703), and abdominal aortic aneurysm (n = 481) from our Department of Vascular and Endovascular Surgery (January 2004–December 2018). Vascular tissue samples are continuously processed and characterized to assess tissue morphology, histological quality, cellular composition, inflammation, calcification, neovascularization, and the content of elastin and collagen fibers. Atherosclerotic plaques are further classified in accordance with the American Heart Association (AHA), and plaque stability is determined. In order to assess the quality of RNA from FFPE tissue samples over time (2009–2018), RNA integrity number (RIN) and the extent of RNA fragmentation were evaluated. Expression analysis was performed with two housekeeping genes—glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB)—using TaqMan-based quantitative reverse-transcription polymerase chain reaction (qRT)-PCR. FFPE biospecimens demonstrated unaltered RNA stability over time for up to 10 years. Furthermore, we provide a protocol for processing tissue samples in our Munich Vascular Biobank. In this work, we demonstrate that biobanking is an important tool not only for scientific research but also for clinical usage and personalized medicine.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Graff, RE, et al.
(författare)
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2Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by TMPRSS2:ERG status.
- 2016
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Ingår i: JOURNAL OF CLINICAL ONCOLOGY. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 34:2
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- 93 Background: Experimental studies have shown that androgen receptor stimulation can facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase the risk of developing TMPRSS2:ERG positive prostate cancer specifically. Methods: We conducted a nested case-control study of 200 prostate cancer cases and 1,057 controls from the Physicians’ Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2:ERG status. TMPRSS2:ERG was assessed by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of fusion-positive (n = 94) and, separately, fusion-negative (n = 106) disease. Results: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86-1.38) (p-diff: 0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive versus ERG-negative disease. Conclusions: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2:ERG positive prostate cancer but are not associated with prostate cancer that lacks TMPRSS2:ERG.
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| 13. |
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| 14. |
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| 15. |
- Meisner, J., et al.
(författare)
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Support for standardisation of high voltage testing with composite and combined wave shapes
- 2021
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Ingår i: VDE High Voltage Technology. - : VDE Verlag GmbH. - 9783800753550 ; , s. 354-358
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Konferensbidrag (refereegranskat)abstract
- As part of the production of equipment for high voltage electricity grids, high voltage tests are performed to verify that the equipment can withstand the operational voltage stresses. Such 'withstand tests' are performed using combined and composite waves, where lightning impulse (LI) or switching impulse (SI) waves are superimposed on AC or DC. Both the technical understanding of the generation and measurement of such high voltage wave forms and the regulations in international standards are not sufficient for the current requirements. Therefore, a European metrology project with industrial partners, universities and seven European metrology institutes (NMI) is started in 2020. In three technical work packages the metrological and standardisation need will be issued. First, the relationship between impulse voltages with AC or DC measurement, and related detrimental effects due to combining wave shape tests will be reliably determined. New measurement instruments, low voltage generators and measurement evaluation software will be created. Traceable high voltage measurement systems and calibration services for composite and combined wave shapes, with a target amplitude uncertainty of less than 2 % will be developed at the NMIs. The capabilities of these NMIs will be confirmed with aid of a high voltage comparison campaign at PTB. The uncertainty of existing voltage dividers and measuring systems used in tests with composite and combined wave shapes will be accurately determined. Finally, the research results will be forwarded to the ongoing revision of the IEC 60060 series.
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| 16. |
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| 17. |
- Saag, K. G., et al.
(författare)
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Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis
- 2017
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 377:15, s. 1417-1427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1: 1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by openlabel alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in >= 330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronateto-alendronate group (11.9% [ 243 of 2047 patients]) (P< 0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P< 0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [ 10.6%]; P = 0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P = 0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials. gov number, NCT01631214.)
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| 18. |
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| 19. |
- Bilde, Trine, et al.
(författare)
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Sex differences in the genetic architecture of lifespan in a seed beetle : extreme inbreeding extends male lifespan
- 2009
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 9, s. 33-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in lifespan are ubiquitous throughout the animal kingdom but the causes underlying this phenomenon remain poorly understood. Several explanations based on asymmetrical inheritance patterns (sex chromosomes or mitochondrial DNA) have been proposed, but these ideas have rarely been tested experimentally. Alternatively, sexual dimorphism in lifespan could result from sex-specific selection, caused by fundamental differences in how males and females optimize their fitness by allocating resources into current and future reproduction. Results: Here we used sex-specific responses to inbreeding to study the genetic architecture of lifespan and mortality rates in Callosobruchus maculatus, a seed beetle that shows sexual dimorphism in lifespan. Two independent assays revealed opposing sex-specific responses to inbreeding. The combined data set showed that inbred males live longer than outbred males, while females show the opposite pattern. Both sexes suffered reduced fitness measured as lifetime reproductive success as a result of inbreeding. Conclusion: No model based on asymmetrical inheritance can explain increased male lifespan in response to inbreeding. Our results are however compatible with models based on sex-specific selection on reproductive strategies. We therefore suggest that sex-specific differences in lifespan in this species primarily result from sexually divergent selection.
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| 20. |
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| 21. |
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| 22. |
- Hallstrom, J., et al.
(författare)
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Performance of a modular wideband 1000 kV HVDC reference divider
- 2014
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Ingår i: CPEM Digest (Conference on Precision Electromagnetic Measurements). - 9781479952052 ; , s. 782-783
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Konferensbidrag (refereegranskat)abstract
- This paper describes the performance of a wideband HVDC reference divider. The divider concept is a shielded modular divider and it is intended for traceable calibration of HVDC measuring systems up to 1000 kV in customers' laboratories. The first priority in the design was the accuracy of HVDC measurements. In addition, the divider was designed to have wide bandwidth, both to enable measurement of ripple voltages and to prevent damage during possible flashovers. © 2014 IEEE.
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| 23. |
- Heusermann, W, et al.
(författare)
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Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER
- 2016
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 213:2, s. 173-184
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Tidskriftsartikel (refereegranskat)abstract
- Exosomes are nanovesicles released by virtually all cells, which act as intercellular messengers by transfer of protein, lipid, and RNA cargo. Their quantitative efficiency, routes of cell uptake, and subcellular fate within recipient cells remain elusive. We quantitatively characterize exosome cell uptake, which saturates with dose and time and reaches near 100% transduction efficiency at picomolar concentrations. Highly reminiscent of pathogenic bacteria and viruses, exosomes are recruited as single vesicles to the cell body by surfing on filopodia as well as filopodia grabbing and pulling motions to reach endocytic hot spots at the filopodial base. After internalization, exosomes shuttle within endocytic vesicles to scan the endoplasmic reticulum before being sorted into the lysosome as their final intracellular destination. Our data quantify and explain the efficiency of exosome internalization by recipient cells, establish a new parallel between exosome and virus host cell interaction, and suggest unanticipated routes of subcellular cargo delivery.
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| 24. |
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| 25. |
- Nordin, Joel Z., et al.
(författare)
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Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties
- 2015
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Ingår i: Nanomedicine. - : Elsevier BV. - 1549-9634 .- 1549-9642. ; 11:4, s. 879-883
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading toadifferent in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs.
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| 26. |
- Paolini, Lucia, et al.
(författare)
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Large-scale production of extracellular vesicles: Report on the “massivEVs” ISEV workshop
- 2022
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Ingår i: Journal of Extracellular Biology. - : Wiley. - 2768-2811. ; 1:10
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) large-scale production is a crucial point for the translation of EVs from discovery to application of EV-based products. In October 2021, the International Society for Extracellular Vesicles (ISEV), along with support by the FET-OPEN projects, “The Extracellular Vesicle Foundry” (evFOUNDRY) and “Extracellular vesicles from a natural source for tailor-made nanomaterials” (VES4US), organized a workshop entitled “massivEVs” to discuss the potential challenges for translation of EV-based products. This report gives an overview of the topics discussed during “massivEVs”, the most important points raised, and the points of consensus reached after discussion among academia and industry representatives. Overall, the review of the existing EV manufacturing, upscaling challenges and directions for their resolution highlighted in the workshop painted an optimistic future for the expanding EV field.
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