| 1. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
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| 3. |
- Drake, Thomas M., et al.
(författare)
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Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction
- 2019
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 45:12, s. 2319-2324
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology Introduction: Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods: A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results: 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions: Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.
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| 4. |
- Hsiao, Tiger Yu-Yang, et al.
(författare)
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JWST Reveals a Possible z similar to 11 Galaxy Merger in Triply Lensed MACS0647-JD
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 949:2
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Tidskriftsartikel (refereegranskat)abstract
- MACS0647-JD is a triply lensed z similar to 11 galaxy originally discovered with the Hubble Space Telescope. The three lensed images are magnified by factors of similar to 8, 5, and 2 to AB mag 25.1, 25.6, and 26.6 at 3.5 mu m. The brightest is over a magnitude brighter than other galaxies recently discovered at similar redshifts z > 10 with JWST. Here, we report new JWST imaging that clearly resolves MACS0647-JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. The brighter larger component "A" is intrinsically very blue (ss similar to-2.6 +/- 0.1), likely due to very recent star formation and no dust, and is spatially extended with an effective radius similar to 70 +/- 24 pc. The smaller component "B" (r similar to 20-+ 58 pc) appears redder (ss similar to-2 +/- 0.2), likely because it is older (100-200 Myr) with mild dust extinction (AV similar to 0.1 mag). With an estimated stellar mass ratio of roughly 2:1 and physical projected separation similar to 400 pc, we may be witnessing a galaxy merger 430 million years after the Big Bang. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be dissimilar, which is also suggested by the spectral energy distribution fitting, suggesting they formed further apart. We also identify a candidate companion galaxy "C" similar to 3 kpc away, likely destined to merge with A and B. Upcoming JWST Near Infrared Spectrograph observations planned for 2023 January will deliver spectroscopic redshifts and more physical properties for these tiny magnified distant galaxies observed in the early universe.
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| 5. |
- Cammareri, Patrizia, et al.
(författare)
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Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5 +ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5 +ve cells also results in cSCC development. These findings indicate that LGR5 +ve stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
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| 6. |
- Gafar, Fajri, et al.
(författare)
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Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents : a systematic review and individual patient data meta-analysis
- 2023
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 61:3
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Forskningsöversikt (refereegranskat)abstract
- Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
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| 7. |
- Malik, R., et al.
(författare)
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Factors associated with breast cancer awareness and breast self-examination in Fiji and Kashmir India - a cross-sectional study
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn low-income countries breast cancer awareness (BCA) is essential to reduce the proportion of advanced stage presentations of breast cancer. There is a lack of studies using multivariable techniques to explore factors related to BCA in low-income countries. The objective of this study was to identify to what extent women in Fiji and Kashmir, India have BCA and practice breast self-examination (BSE) as well as factors associated with BCA and BSE.MethodsA survey of women aged >= 18years was conducted in Fiji and Kashmir, India to assess BCA and rates of BSE. Comparison between Fiji and Kashmir was done using student's t-test for continuous data and chi-square for binary data. Factors associated with BCA and BSE were analysed using a multivariable logistic regression for Fiji and Kashmir separately.ResultsData were collected from 399 and 1982 women in Kashmir and Fiji, respectively. Of 1968 women in Fiji 57% were deemed to have an acceptable BCA compared to only 7.3% of 395 women in Kashmir. Having some education was associated with having BCA with an odds ratio of 4.7 (1.7-13) in Fiji and 10 (1.7-59) in Kashmir. Of 1976 women in Fiji 40% had tertiary education while 40% of 392 women in Kashmir had no education at all. The marital status was similar in both samples (n=1973 and 395) with 68-69% being married and 21-26% being single. The lack of female doctors or nurses with whom to discuss issues, was perceived as a problem in both countries.ConclusionsThe key finding is an association between having any level of education and BCA. This correlation was much stronger than for a family history of breast cancer and BCA. Hence, general education to illiterate women may reduce the proportion of women in low-income countries presenting with advanced-stage breast cancer.
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| 8. |
- Barker, Roger A., et al.
(författare)
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Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25, s. 1045-1053
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Tidskriftsartikel (refereegranskat)abstract
- Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
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| 9. |
- Lahiri, A. K., et al.
(författare)
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Foam in iron and steelmaking
- 2004
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Ingår i: High Temperature Materials and Processes. - : Walter de Gruyter GmbH. - 0334-6455 .- 2191-0324. ; 22:06-maj, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- Foam is common in iron and steelmaking processes. Iron and steelmaking slags have inherent foaminess but the presence of strong surface active compounds like P2O5, Cr2O3, CaS, V2O5 and CaF2 make the foam more stable. Stable foam can form only in the presence of surface active agents. When a bubble rises on the surface of a liquid, the film around it develops a concentration gradient of surface active agents such that Marangoni force acts in upward direction. This prevents liquid drainage from the film. The presence of surface active agents favours fort-nation of smaller bubbles and prevents bubble rupture as well. So a strong surface active agent where dsigma/dc is high makes the foam very stable. When a bubble comes into contact with a solid surface, the dynamic contact angle is different from the equilibrium value. If the former is less than the latter, there is a resultant outward force which tries to make the bubble flat. This force is responsible for the collapse of foamy slags in the presence of large carbonaceous particles. This force is not significant for very small bubbles and is not effective when carbon particles are much smaller than the bubble.
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| 10. |
- Meena, Ashish Kumar, et al.
(författare)
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Two Lensed Star Candidates at z similar or equal to 4.8 behind the Galaxy Cluster MACS J0647.7+7015
- 2023
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Ingår i: Astrophysical Journal Letters. - : Institute of Physics (IOP). - 2041-8205 .- 2041-8213. ; 944:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of two extremely magnified lensed star candidates behind the galaxy cluster MACS J0647.7+015 using recent multiband James Webb Space Telescope (JWST) NIRCam observations. The star candidates are seen in a previously known, z (phot) similar or equal to 4.8 dropout giant arc that straddles the critical curve. The candidates lie near the expected critical curve position, but lack clear counter-images on the other side of it, suggesting these are possibly stars undergoing caustic crossings. We present revised lensing models for the cluster, including multiply imaged galaxies newly identified in the JWST data, and use them to estimate background macro-magnifications of at least greater than or similar to 90 and greater than or similar to 50 at the positions of the two candidates, respectively. With these values, we expect effective, caustic-crossing magnifications of similar to[10(3)-10(5)] for the two star candidates. The spectral energy distributions of the two candidates match well the spectra of B-type stars with best-fit surface temperatures of similar to 10,000 K, and similar to 12,000 K, respectively, and we show that such stars with masses greater than or similar to 20 M (circle dot) and greater than or similar to 50 M (circle dot), respectively, can become sufficiently magnified to be observable. We briefly discuss other alternative explanations and conclude that these objects are likely lensed stars, but also acknowledge that the less-magnified candidate may alternatively reside in a star cluster. These star candidates constitute the second highest-redshift examples to date after Earendel at z (phot) similar or equal to 6.2, establishing further the potential of studying extremely magnified stars at high redshifts with JWST. Planned future observations, including with NIRSpec, will enable a more detailed view of these candidates in the near future.
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