| 1. |
- Hollestelle, Antoinette, et al.
(author)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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In: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Journal article (peer-reviewed)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 2. |
- Lawrenson, Kate, et al.
(author)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 3. |
- Wade, G. A., et al.
(author)
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The MiMeS survey of magnetism in massive stars : introduction and overview
- 2016
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 456:1, s. 2-22
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Journal article (other academic/artistic)abstract
- The MiMeS (Magnetism in Massive Stars) project is a large-scale, high-resolution, sensitive spectropolarimetric investigation of the magnetic properties of O- and early B-type stars. Initiated in 2008 and completed in 2013, the project was supported by three Large Program allocations, as well as various programmes initiated by independent principal investigators, and archival resources. Ultimately, over 4800 circularly polarized spectra of 560 O and B stars were collected with the instruments ESPaDOnS (Echelle SpectroPolarimetric Device for the Observation of Stars) at the Canada-France-Hawaii Telescope, Narval at the Telescope Bernard Lyot and HARPSpol at the European Southern Observatory La Silla 3.6 m telescope, making MiMeS by far the largest systematic investigation of massive star magnetism ever undertaken. In this paper, the first in a series reporting the general results of the survey, we introduce the scientific motivation and goals, describe the sample of targets, review the instrumentation and observational techniques used, explain the exposure time calculation designed to provide sensitivity to surface dipole fields above approximately 100 G, discuss the polarimetric performance, stability and uncertainty of the instrumentation, and summarize the previous and forthcoming publications.
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| 4. |
- Hubrig, Swetlana, et al.
(author)
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Magnetic fields in O-type stars measured with FORS 1 at the VLT
- 2009
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In: Cosmic Magnetic Fields: From Planets, to Stars and Galaxies, Proceedings of the International Astronomical Union. ; 259, s. 381-382, s. 381-382
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Journal article (other academic/artistic)abstract
- The presence of magnetic fields in O-type stars has been suspected for a long time. The discovery of such fields would explain a wide range of well documented enigmatic phenomena in massive stars, in particular cyclical wind variability, Hα emission variations, chemical peculiarity, narrow X-ray emission lines and non-thermal radio/X-ray emission. Here we present the results of our studies of magnetic fields in O-type stars, carried out over the last years.
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| 5. |
- Shultz, M. E., et al.
(author)
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Ultraviolet spectropolarimetry with Polstar : using Polstar to test magnetospheric mass-loss quenching
- 2022
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In: Astrophysics and Space Science. - : Springer Nature. - 0004-640X .- 1572-946X. ; 367:12
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Journal article (peer-reviewed)abstract
- Polstar is a proposed NASA MIDEX space telescope that will provide high-resolution, simultaneous full-Stokes spectropolarimetry in the far ultraviolet, together with low-resolution linear polarimetry in the near ultraviolet. This observatory offers unprecedented capabilities to obtain unique information on the magnetic and plasma properties of the magnetospheres of hot stars. We describe an observing program making use of the known population of magnetic hot stars to test the fundamental hypothesis that magnetospheres should act to rapidly drain angular momentum, thereby spinning the star down, whilst simultaneously reducing the net mass-loss rate. Both effects are expected to lead to dramatic differences in the evolution of magnetic vs. non-magnetic stars.
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| 6. |
- Wynberg, Elke, et al.
(author)
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Variability in white blood cell count during uncomplicated malaria and implications for parasite density estimation : a WorldWide Antimalarial Resistance Network individual patient data meta-analysis
- 2023
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In: Malaria Journal. - : Springer Nature. - 1475-2875. ; 22
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Journal article (peer-reviewed)abstract
- Background: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood sample is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance.Methods: Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an individual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/mu L and age-stratified values) using estimates derived from the measured WBC value as reference.Results: Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (x 1000 cells/mu L) in age groups < 1, 1-4, 5-14 and >= 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for individuals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for individuals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/mu L resulted in parasite density underestimation by a median (IQR) of 26% (4-41%) in infants < 1 year old but an overestimation by 50% (16-91%) in adults aged = 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve precision of parasitaemia estimation. Imprecision of parasite clearance estimates was only affected by the within-patient WBC variability over time, and remained < 10% for 79% of patients.Conclusions: Using an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management; but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.
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| 7. |
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| 8. |
- Concin, Nicole, et al.
(author)
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European Society of Gynaecological Oncology quality indicators for the surgical treatment of endometrial carcinoma
- 2021
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In: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. - : BMJ. - 1048-891X. ; 31:12, s. 1508-1529
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Journal article (peer-reviewed)abstract
- BACKGROUND: Quality of surgical care as a crucial component of a comprehensive multi-disciplinary management improves outcomes in patients with endometrial carcinoma, notably helping to avoid suboptimal surgical treatment. Quality indicators (QIs) enable healthcare professionals to measure their clinical management with regard to ideal standards of care. OBJECTIVE: In order to complete its set of QIs for the surgical management of gynecological cancers, the European Society of Gynaecological Oncology (ESGO) initiated the development of QIs for the surgical treatment of endometrial carcinoma. METHODS: QIs were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for the identification of potential QIs and documentation of the scientific evidence, two consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians and patient representatives. QIs were defined using a structured format comprising metrics specifications, and targets. A scoring system was then developed to ensure applicability and feasibility of a future ESGO accreditation process based on these QIs for endometrial carcinoma surgery and support any institutional or governmental quality assurance programs. RESULTS: Twenty-nine structural, process and outcome indicators were defined. QIs 1-5 are general indicators related to center case load, training, experience of the surgeon, structured multi-disciplinarity of the team and active participation in clinical research. QIs 6 and 7 are related to the adequate pre-operative investigations. QIs 8-22 are related to peri-operative standards of care. QI 23 is related to molecular markers for endometrial carcinoma diagnosis and as determinants for treatment decisions. QI 24 addresses the compliance of management of patients after primary surgical treatment with the standards of care. QIs 25-29 highlight the need for a systematic assessment of surgical morbidity and oncologic outcome as well as standardized and comprehensive documentation of surgical and pathological elements. Each QI was associated with a score. An assessment form including a scoring system was built as basis for ESGO accreditation of centers for endometrial cancer surgery.
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| 9. |
- De Kloe, Yentl J.R., et al.
(author)
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Replacing eye trackers in ongoing studies : A comparison of eye‐tracking data quality between the Tobii Pro TX300 and the Tobii Pro Spectrum
- 2021
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In: Infancy. - : Wiley. - 1532-7078 .- 1525-0008.
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Journal article (peer-reviewed)abstract
- The Tobii Pro TX300 is a popular eye tracker in developmental eye-tracking research, yet it is no longer manufactured. If a TX300 breaks down, it may have to be replaced. The data quality of the replacement eye tracker may differ from that of the TX300, which may affect the experimental outcome measures. This is problematic for longitudinal and multi-site studies, and for researchers replacing eye trackers between studies. We, therefore, ask how the TX300 and its successor, the Tobii Pro Spectrum, compare in terms of eye-tracking data quality. Data quality—operationalized through precision, accuracy, and data loss—was compared between eye trackers for three age groups (around 5-months, 10-months, and 3-years). Precision was better for all gaze position signals obtained with the Spectrum in comparison to the TX300. Accuracy of the Spectrum was higher for the 5-month-old and 10-month-old children. For the three-year-old children, accuracy was similar across both eye trackers. Gaze position signals from the Spectrum exhibited lower proportions of data loss, and the duration of the data loss periods tended to be shorter. In conclusion, the Spectrum produces gaze position signals with higher data quality, especially for the younger infants. Implications for data analysis are discussed.
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| 10. |
- Hessels, Roy S, et al.
(author)
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Eye contact avoidance in crowds : A large wearable eye-tracking study
- 2022
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In: Attention, Perception & Psychophysics. - : Springer Science and Business Media LLC. - 1943-3921 .- 1943-393X. ; 84:8, s. 2623-2640
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Journal article (peer-reviewed)abstract
- Eye contact is essential for human interactions. We investigated whether humans are able to avoid eye contact while navigating crowds. At a science festival, we fitted 62 participants with a wearable eye tracker and instructed them to walk a route. Half of the participants were further instructed to avoid eye contact. We report that humans can flexibly allocate their gaze while navigating crowds and avoid eye contact primarily by orienting their head and eyes towards the floor. We discuss implications for crowd navigation and gaze behavior. In addition, we address a number of issues encountered in such field studies with regard to data quality, control of the environment, and participant adherence to instructions. We stress that methodological innovation and scientific progress are strongly interrelated.
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| 11. |
- Lindemann, Kristina, et al.
(author)
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Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)
- 2014
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
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Journal article (peer-reviewed)abstract
- Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients.
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| 12. |
- Mertens, Fredrik, et al.
(author)
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The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4.
- 2011
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 128, s. 487-491
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Journal article (peer-reviewed)abstract
- Subungual exostosis is a benign bone- and cartilage-forming tumor known to harbour a pathognomonic t(X;6)(q22;q13-14). Using global gene expression analysis and quantitative real-time PCR we could show that this translocation results in increased expression of the IRS4 gene, presumably due to disruption and/or exchange of regulatory sequences with the translocation partner, the COL12A1 gene. A corresponding deregulation at the protein level could be demonstrated in primary cell cultures using a combination of fluorescence in situ hybridization and immunostaining. As the t(X;6) usually is the sole cytogenetic aberration in subungual exostosis, the deregulated expression of IRS4 is likely to be pathogenetically essential. The exact role of IRS4 is still poorly investigated, but IRS proteins are known to act as mediators of signalling from receptors, such as the insulin and insulin-like growth factor 1 receptors, and thus have an important effect on cell growth and survival. (c) 2010 UICC.
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| 13. |
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| 14. |
- Schouten, Wietse M., et al.
(author)
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Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood
- 2024
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In: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier. - 0731-7085 .- 1873-264X. ; 245
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Journal article (peer-reviewed)abstract
- Malaria remains a major health concern, aggravated by emerging resistance of the parasite to existing treatments. The World Health Organization recently endorsed the use of artesunate-pyronaridine to treat uncomplicated malaria. However, there is a lack of clinical pharmacokinetic (PK) data of pyronaridine, particularly in special populations such as children and pregnant women. Existing methods for the quantification of pyronaridine in biological matrices to support PK studies exhibit several drawbacks. These include limited sensitivity, a large sample volume required, and extensive analysis time. To overcome these limitations, an ultra-performance reversed-phase liquid chromatography tandem-mass spectrometry method to determine pyronaridine was developed and validated according to international guidelines. The method enabled fast and accurate quantification of pyronaridine in whole blood across a clinically relevant concentration range of 0.500-500 ng/mL (r2 >= 0.9963), with a required sample volume of 50 mu L. Pyronaridine was extracted from whole blood using liquidliquid extraction, effectively eliminating the matrix effect and preventing ion enhancement or suppression. The method achieved a satisfactory reproducible sample preparation recovery of 77%, accuracy (as bias) and precision were within +/- 8.2% and <= 5.3%, respectively. Stability experiments demonstrated that pyronaridine was stable for up to 315 days when stored at - 70 degrees C. Adjustments to the chromatographic system substantially reduced carry-over and improved sensitivity compared to prior methods. The method was successfully applied to quantify pyronaridine in whole blood samples from a selection of pregnant malaria patients participating in the PYRAPREG clinical trial (PACTR202011812241529) in the Democratic Republic of the Congo, demonstrating its suitability to support future PK studies. Furthermore, the enhanced sensitivity allows for the determination of pyronaridine up to 42 days post-treatment initiation, enabling assessment of the terminal elimination half-life.
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| 15. |
- Verrest, Luka, et al.
(author)
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Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis
- 2023
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 78:11, s. 2702-2714
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Journal article (peer-reviewed)abstract
- Objectives: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.Methods: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.Results: Data from 265 patients (59% & LE;12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) & mu;g & BULL;h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) & mu;g & BULL;day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults.Conclusions: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
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