| 1. |
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| 2. |
- Emerging Risk Factors, Collaboration, et al.
(författare)
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The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases
- 2007
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Ingår i: Eur J Epidemiol. - 0393-2990. ; 22:12, s. 839-69
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Tidskriftsartikel (refereegranskat)abstract
- Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
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| 3. |
- Kaptoge, S., et al.
(författare)
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World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions
- 2019
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Ingår i: Lancet Global Health. - : Elsevier BV. - 2214-109X. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Background To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. Methods In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. Findings Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0.685 (95% CI 0 . 629-0 741) to 0.833 (0 . 783-0- 882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. Interpretation We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
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| 4. |
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| 5. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 6. |
- Gregson, J., et al.
(författare)
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Cardiovascular Risk Factors Associated With Venous Thromboembolism
- 2019
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Ingår i: JAMA Cardiology. - : American Medical Association (AMA). - 0965-2590 .- 2380-6583 .- 2380-6591. ; 4:2, s. 163-173
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE Older age, smoking, and adiposity were consistently associated with higher VTE risk.
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| 7. |
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| 8. |
- Arroyo-Yanguas, Yolanda, et al.
(författare)
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Binding, internalization, and degradation of antiproliferative heparan sulfate by human embryonic lung fibroblasts
- 1997
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Ingår i: Journal of Cellular Biochemistry. - 0730-2312. ; 64:4, s. 595-604
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Tidskriftsartikel (refereegranskat)abstract
- Binding, internalization, and degradation of 125I-labeled, antiproliferative, or nonantiproliferative heparan sulfate by human embryonic lung fibroblasts was investigated. Both L-iduronate-rich, antiproliferative heparan sulfate species as well as L-iduronate-poor, inactive ones were bound to trypsin-releasable, cell-surface sites. Both heparan sulfate types were bound with approximately the same affinity to one high-affinity site (Kd approximately 10(-8) M) and to one low-affinity site (Kd approximately 10(-6) M), respectively. Results of Hill-plot analysis suggested that the two sites are independent. Competition experiments with unlabeled glycosaminoglycans indicated that the binding sites had a selective specificity for sulfated, L-iduronate-rich heparan sulfate. Dermatan sulfate, which is also antiproliferative, was weakly bound to the cells. The antiproliferative effects of heparan and dermatan sulfate appeared to be additive. Hence, the two glycosaminoglycans probably exert their effect through different mechanisms. At concentrations above 5 micrograms/ml (approximately 10(-7) M), heparan sulfate was taken up by human embryonic lung fibroblasts, suggesting that the low-affinity site represents an endocytosis receptor. The antiproliferative effect of L-iduronate-rich heparan sulfate species was also exerted at the same concentrations. The antiproliferative species was taken up to a greater degree than the inactive one, suggesting a requirement for internalization. However, competition experiments with dextran sulfate suggested that both the high-affinity and the low-affinity sites are involved in mediating the antiproliferative effect. Structural analysis of the inactive and active heparan sulphate preparations indicated that although sulphated L-iduronate appears essential for antiproliferative activity, it is not absolutely required for binding to the cells. Degradation of internalized heparan sulfate was analyzed by polyacrylamide gel electrophoresis using a sensitive detection technique. The inactive species was partially degraded, whereas the antiproliferative one was only marginally affected.
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| 9. |
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| 10. |
- Cesano, A, et al.
(författare)
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Society for Immunotherapy of Cancer clinical and biomarkers data sharing resource document: Volume II-practical challenges
- 2020
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- The development of strongly predictive validated biomarkers is essential for the field of immuno-oncology (IO) to advance. The highly complex, multifactorial data sets required to develop these biomarkers necessitate effective, responsible data-sharing efforts in order to maximize the scientific knowledge and utility gained from their collection. While the sharing of clinical- and safety-related trial data has already been streamlined to a large extent, the sharing of biomarker-aimed clinical trial derived data and data sets has been met with a number of hurdles that have impaired the progression of biomarkers from hypothesis to clinical use. These hurdles include technical challenges associated with the infrastructure, technology, workforce, and sustainability required for clinical biomarker data sharing. To provide guidance and assist in the navigation of these challenges, the Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to outline the challenges that researchers currently face, both at the conceptual level (Volume I) and at the technical level (Volume II). The committee also suggests possible solutions to these problems in the form of professional standards and harmonized requirements for data sharing, assisting in continued progress toward effective, clinically relevant biomarkers in the IO setting.
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| 11. |
- Rutella, S, et al.
(författare)
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Society for Immunotherapy of Cancer clinical and biomarkers data sharing resource document: Volume I-conceptual challenges
- 2020
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- The sharing of clinical trial data and biomarker data sets among the scientific community, whether the data originates from pharmaceutical companies or academic institutions, is of critical importance to enable the development of new and improved cancer immunotherapy modalities. Through data sharing, a better understanding of current therapies in terms of their efficacy, safety and biomarker data profiles can be achieved. However, the sharing of these data sets involves a number of stakeholder groups including patients, researchers, private industry, scientific journals and professional societies. Each of these stakeholder groups has differing interests in the use and sharing of clinical trial and biomarker data, and the conflicts caused by these differing interests represent significant obstacles to effective, widespread sharing of data. Thus, the Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify the current barriers to biomarker data sharing in immuno-oncology (IO) and to help in establishing professional standards for the responsible sharing of clinical trial data. The conclusions of the committee are described in two position papers: Volume I—conceptual challenges and Volume II—practical challenges, the first of which is presented in this manuscript. Additionally, the committee suggests actions by key stakeholders in the field (including organizations and professional societies) as the best path forward, encouraging the cultural shift needed to ensure responsible data sharing in the IO research setting.
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| 12. |
- Westergren-Thorsson, G, et al.
(författare)
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L-iduronate-rich glycosaminoglycans inhibit growth of normal fibroblasts independently of serum or added growth factors
- 1993
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 206:1, s. 9-93
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Tidskriftsartikel (refereegranskat)abstract
- The effects of various glycosaminoglycans (GAGs) on the growth rate of normal fibroblasts and a fibrosarcoma cell line (HT 1080) were examined. Cells were grown in 96-well microplates in the absence or presence of serum mitogens, epidermal (EGF), platelet-derived (PDGF), acidic fibroblast (aFGF), or basic fibroblast growth factor (bFGF). Cell number was measured by using crystal violet to stain cell nuclei (Westergren-Thorsson, G., Onnervik, P.-O., Fransson, L.-A., and Malmström, A. J. Cell. Phys. 147, 523-530, 1991) and also by using a Coulter counter. In the presence of serum mitogens, L-iduronate (IdoA)-rich GAGs, such as dermatan sulfate, heparin, and highly sulfated heparan sulfate, inhibited proliferation of normal cells (25-35%), whereas HT 1080 cells were unaffected or slightly stimulated. Ham's F-12 supplemented with insulin and transferrin but without growth factors was able to support growth of both cell types. Under these conditions, the IdoA-rich GAGs still suppressed growth of normal cells (40-55%), whereas HT 1080 cells again responded poorly. When growth factors were added proliferation of normal fibroblasts was further stimulated, EGF being the most effective. In the presence of either EGF, PDGF, or bFGF, IdoA-rich GAGs had a sustained inhibitory effect on normal fibroblasts (30-50% at concentrations at or above 10 micrograms/ml). However, in the presence of aFGF, both IdoA-rich and IdoA-poor heparan sulfates enhanced growth (nearly twofold after prolonged exposure) suggesting a stabilization of this growth factor. In general, IdoA-rich GAGs appear to inhibit proliferation of normal cells irrespective of the type of growth factor used. Therefore, GAGs are likely to act directly on cell-derived regulatory components, either before or after internalization. As fibrosarcoma cells were much less sensitive to growth inhibition, they may contain altered receptors for GAGs.
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| 13. |
- Aminipouri, M., et al.
(författare)
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Urban tree planting to maintain outdoor thermal comfort under climate change: The case of Vancouver's local climate zones
- 2019
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Ingår i: Building and Environment. - : Elsevier BV. - 0360-1323. ; 158, s. 226-236
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Tidskriftsartikel (refereegranskat)abstract
- Spatiotemporal variation of mean radiant temperature (Tmrt), a major driver of outdoor human thermal comfort, is driven by exposure to solar and longwave radiation, which in turn respond to local patterns of shading, wind speed, air humidity and air temperature. In this study, the SOlar and LongWave Environmental Irradiance Geometry (SOLWEIG) model was used to simulate how changes in minimum and maximum air temperature and solar radiation under Representative Concentration Pathways (RCP) 4.5 and 8.5 climate projections would change Tmrt in Vancouver over the 2070-2100 period. With micrometeorological variables representative of a changed climate, days with Tmrt above 65 degrees C were predicted to increase three-to five-fold under RCP 4.5 and 8.5, respectively. SOLWEIG was also used to quantify the potential of maximum feasible street tree cover to reduce Tmrt for the hottest day on record for Vancouver (July 29, 2009), and an end-of-century hot day under the two future climate scenarios. SOLWEIG simulations with maximum feasible street tree cover under RCP 4.5 demonstrated an average reduction of 1.3 degrees C in Tmrt, compared to the contemporary extreme heat day with current street trees. However, average Tmrt increased by 1.9 degrees C under the RCP 8.5 scenario even with maximum feasible street tree cover, relative to the contemporary extreme heat day. We conclude that adding street trees has the potential to offset Tmrt increases under the RCP 4.5 scenario, however this measure is insufficient to maintain contemporary Tmrt under the RCP 8.5 scenario.
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| 14. |
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| 15. |
- Drouin-Ouellet, Janelle, et al.
(författare)
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REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways
- 2017
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:8, s. 1117-1131
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Tidskriftsartikel (refereegranskat)abstract
- Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.
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| 16. |
- Eiken, Ola, et al.
(författare)
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Human skeletal muscle function and metabolism during intense exercise at high O2 and N2 pressures
- 1987
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 63:2, s. 571-575
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Tidskriftsartikel (refereegranskat)abstract
- The maximal contractile force (peak torque) of the quadriceps femoris was studied during 60 repeated unilateral dynamic knee extensions in nine subjects under three different conditions, viz., during air breathing at normal (1 ATA) and raised (6 ATA) ambient pressures and during O2 breathing at 1.3 ATA. In six subjects the electromyographic (EMG) activity of the working muscle was recorded. Muscle biopsies were obtained from the vastus lateralis before, immediately after, and 1 min after exercise. Tissue specimens were subsequently assayed for various muscle metabolites. Peak torque, as an average of the 60 knee extensions, was higher (P less than 0.05) at 1.3 ATA than at 6 or 1 ATA. Peak torque of the exercising muscle declined more rapidly at 1 ATA than at 1.3 ATA, differing in the final 24 contractions by 14%. At 6 ATA peak torque of the initial 12 contractions was 6% lower (P less than 0.05) than at 1 ATA but equaled 1-ATA values in the latter third of the exercise bout. Although the EMG activity at 1 ATA increased relative to that at 6 ATA as exercise proceeded, the rate of force decline was greater at 1 ATA. Despite greater total work produced at 1.3 ATA than at 1 ATA, the metabolic response to exercise was not substantially altered at increased O2 pressure. However, the restitution rate of energy-rich phosphagens and the elimination of lactate during recovery were greater (P less than 0.05) at 1.3 ATA. These results suggest that hyperoxia may enhance the rate of energy release, whereas high N2 pressure and/or high hydrostatic pressure seem to interfere with neuromuscular activity.
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| 17. |
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| 18. |
- Juhasz, P., et al.
(författare)
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ESI and MALDI LC/MS-MS approaches for large scale protein, identification and quantification : Are they equivalent?
- 2002
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Ingår i: ; , s. 55-56
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Konferensbidrag (refereegranskat)abstract
- An approach for large scale protein identification and quantification was described. The peptide mixtures from the strong cation exchange (SCX) fractionated protein digests were separated and analyzed by HPLC MS/MS. The human fibrobalst nuclei were purified from stimulated and non-stimulated cells. The quantification results with MALDI and ESI LC/MS were shown to be identical within experimental error.
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| 19. |
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| 20. |
- Mani, K, et al.
(författare)
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Heparan/chondroitin/dermatan sulfate primer 2-(6-hydroxynaphthyl)-O-beta-D-xylopyranoside preferentially inhibits growth of transformed cells
- 1998
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Ingår i: Cancer Research. - 0008-5472. ; 58:6, s. 104-1099
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Tidskriftsartikel (refereegranskat)abstract
- Xylose forms the direct carbohydrate-protein link in extra- or pericellular proteoglycans (PGs) that are substituted with either chondroitin sulfate (CS)/dermatan sulfate (DS) and/or heparan sulfate (HS). Cell surface PGs carrying HS are important regulators of cell growth. Xylose coupled to an aromatic compound can enter cells and initiate either CS/DS synthesis or both HS and CS/DS synthesis, depending on the nature of the aromatic adduct. Here, we show that 2-(6-hydroxynaphthyl)-O-beta-D-xylopyranoside, which can prime both types of glycan chains, inhibits growth of a set of normal and transformed cells. Transformed cells are preferentially inhibited, and at a concentration of 0.15-0.20 mM xyloside, transformed cells are totally growth arrested, whereas normal cells are only < or = 50% inhibited. No inhibition of growth is observed with the stereoisomeric 2-(6-hydroxynaphthyl)-O-beta-L-xylopyranoside, which does not prime glycosaminoglycan synthesis at all; with the nonhydroxylated 2-naphthyl-O-beta-D-xylopyranoside, which only primes CS/DS synthesis under these conditions; or with p-nitrophenyl-O-beta-D-xylopyranoside, which is known to prime only CS/DS synthesis. We conclude that growth inhibition is due to priming of HS and/or CS/DS synthesis, which may either lead to the formation of specific antiproliferative glycans or glycan fragments or to interference with endogenous PG synthesis and turnover.
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| 21. |
- Olafsson, S, et al.
(författare)
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Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
- 2017
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 2, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10−7, 4.3 × 10−9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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| 22. |
- Ritzén, E Martin, et al.
(författare)
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Nordic consensus on treatment of undescended testes.
- 2007
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 96:5, s. 638-643
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To reach consensus among specialists from the Nordic countries on the present state-of-the-art in treatment of undescended testicles. Methods: A group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for two days. Before the meeting, reviews of the literature had been prepared by the participants. Recommendations: The group came to the following unanimous conclusions: (1) In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long term adverse effects on spermatogenesis. Thus, surgery is to be preferred. (2) Orchiopexy should be done between 6 and 12 months of age, or upon diagnosis, if that occurs later. (3) Orchiopexy before age one year should only be done at centres with both paediatric surgeons/urologists and paediatric anaesthesiologists. (4) If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery—to paediatric rather than general surgeons/urologists if the boy is less than one year old or if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- van Tienderen, Gilles S, et al.
(författare)
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Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis.
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| 28. |
- Westergren-Thorsson, G, et al.
(författare)
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Altered dermatan sulfate proteoglycan synthesis in fibroblast cultures established from skin of patients with systemic sclerosis
- 1996
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 23:8, s. 406-1398
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study whether changes in the properties of skin from patients with systemic sclerosis (SSc) are the result of altered metabolism of dermatan sulfate proteoglycans.METHODS: Fibroblast cultures were established from skin of healthy controls, and from affected and unaffected skin of patients with SSc. Synthesized proteoglycans were labeled with 3H glucosamine and 35S sulfate. The amount of mRNA of the different dermatan sulfate proteoglycans was determined by hybridization with the corresponding cDNA probes.RESULTS: A 2-fold increase in secretion of total proteoglycans was found in cell cultures from affected and normal appearing skin from patients with SSc. The production of 2 different dermatan sulfate proteoglycans was increased. Aggrecan/versican increased 4-fold and decorin 2-fold in cultures of affected skin from patients with SSc. The mRNA for decorin increased 3-fold, while the mRNA level for versican increased only slightly. Similar but less marked changes were noted in cultures from normal appearing skin. In contrast, the biglycan mRNA level decreased and the product could only be found in very small amounts in SSc cultures.CONCLUSION: This marked alteration of dermatan sulfate proteoglycan metabolism distinguishes not only affected skin but also normal appearing SSc skin from that of controls. The altered proteoglycan production may affect organization of matrix fibers and thereby the fibrotic process observed in patients with SSc.
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| 29. |
- Westergren-Thorsson, G, et al.
(författare)
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Altered expression of small proteoglycans, collagen, and transforming growth factor-beta 1 in developing bleomycin-induced pulmonary fibrosis in rats
- 1993
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 92:2, s. 7-632
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Tidskriftsartikel (refereegranskat)abstract
- The development of bleomycin-induced pulmonary fibrosis in rats was studied over a period of 21 d after an intratracheal instillation of bleomycin. The expression of three small proteoglycans (biglycan, decorin, and fibromodulin), collagen III and TGF-beta 1 was studied by RNA-transfer blot analysis. The proteoglycans were also studied by SDS-polyacrylamide gel electrophoresis and Western blots. TGF-beta 1 mRNA increased threefold already on day 3 and remained elevated until day 10. After the increase of TGF-beta 1 mRNA the messages for biglycan and collagen III steadily increased to reach a maximum 10 d after bleomycin instillation. The mRNA for biglycan increased maximally fourfold and that of collagen III 2.5-fold. Decorin mRNA, in contrast to biglycan decreased and reached 20% of control on day 10. The message for fibromodulin remained constant throughout the study period. The amounts of biglycan and decorin in the tissue changed in accordance with the mRNA levels. The results corroborate and extend previous in vitro studies concerning the effect of TGF-beta 1 on the metabolism of small proteoglycans and show that these macromolecules are regulated differently also in vivo. The marked alterations of biglycan and decorin during the development of fibrosis suggests that these proteoglycans have a regulating role in this process.
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| 30. |
- Westergren-Thorsson, G, et al.
(författare)
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Proliferation of cultured fibroblasts is inhibited by L-iduronate-containing glycosaminoglycans
- 1991
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541. ; 147:3, s. 30-523
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Tidskriftsartikel (refereegranskat)abstract
- We have modified a method (Gilles et al: Anal. Biochem., 159:109-113, 1986) for measuring cell number, that is based on the binding of crystal violet to cell nuclei and used it to assay effects of various glycosaminoglycans on growth of human lung fibroblasts. The procedure was modified by growing cells in microcultures (96 well microplates) and by measuring the amount of adsorbed dye using a microplate photometer after solubilisation of the cells with detergent. There was a linear relationship between absorbance and cell number measured by a Coulter Counter. The method is rapid and sensitive and can be used for screening many samples as well as measuring growth rates at low initial cell densities. Even the low growth rates obtained in the absence of serum can be detected. Human lung fibroblasts were growth arrested by serum deprivation and then grown for periods of up to 4 days in the presence of serum and exogenously added glycosaminoglycans (range, 0.1-100 micrograms/ml). Hyaluronan, chondroitin sulfate, and dextran sulfate were without effects, whereas dermatan sulfate, certain heparan sulfates, and heparin suppressed growth (20%-50% inhibition). The antiproliferative activity of dermatan sulfate increased with increasing iduronate content. Certain heparan sulfates, with moderately high sulfate and L-iduronate contents were better inhibitors than heparin despite the fact that the latter glycan has even higher sulfate and L-iduronate contents. The antiproliferative effect of exogenous glycans appeared after a lag period of 3-4 days, suggesting that they interfered with factors produced by the cells. Furthermore, the degree of inhibition was greater when the initial cell density was low. Above a certain level of seeded cells (approx. 10,000 cells/well), there was no inhibition by any of the glycosaminoglycans. It is possible that exogenous glycans cannot overcome endogenous growth-promoting effects in densely seeded cultures.
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| 31. |
- Westergren-Thorsson, G, et al.
(författare)
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TGF-beta enhances the production of hyaluronan in human lung but not in skin fibroblasts
- 1990
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 186:1, s. 5-192
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor-beta (TGF-beta) enhances the production of extracellular matrix components, such as type I and type III collagen, fibronectin, proteoglycans, in various cell types. The effect on hyaluronan synthesis in relation to proteoglycan synthesis has not been investigated. Human lung or skin fibroblast cultures were treated with TGF-beta in serum-free medium for various periods of time. 35SO4 or [3H]glucosamine was then added to the cultures in the absence of TGF-beta for up to 48 h. Hyaluronan and proteoglycans were isolated by ion-exchange chromatography and quantitated. TGF-beta induced a three- to fourfold increase in hyaluronan production by lung cells but had no effect on skin fibroblasts. In contrast, proteoglycan synthesis was enhanced in both cell types, although skin fibroblasts responded at lower concentrations of TGF-beta. Increased accumulation of hyaluronan was noted only in the cell medium, whereas proteoglycan accumulation was observed both in the medium and in the cell layer. The ED50 for TGF-beta on hyaluronan accumulation in lung cells was the same as that for proteoglycan accumulation, i.e., 40 pM. In skin fibroblasts the ED50 was considerably lower (4 pM). The induction time needed to attain full effect of TGF-beta was 6 h for both hyaluronan and proteoglycan synthesis. These results indicate that TGF-beta has tissue-specific effects on matrix production which may be of importance for control of cell proliferation in various disease states.
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| 32. |
- Westergren-Thorsson, G, et al.
(författare)
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The synthesis of a family of structurally related proteoglycans in fibroblasts is differently regulated by TFG-beta
- 1991
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Ingår i: Matrix (Stuttgart, Germany). - 0934-8832. ; 11:3, s. 83-177
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblasts synthesize a variety of proteoglycans among which is a family of structurally related small proteoglycans, i.e. PG-S1 (biglycan) and PG-S2 (decorin). Fibromodulin, which is present in some tissues as a keratan sulfate proteoglycan, also belongs to this family. We have used primary fibroblasts from fetal skin and bovine sclera in culture to study the metabolism of proteoglycans. In particular the regulatory effect of transforming growth factor-beta (TGF-beta), interleukin-1 (IL-1) platelet-derived growth factor (PDGF) and dexamethasone was determined by studies of mRNA levels for these structurally related proteoglycans. Furthermore the synthesis and secretion of these macromolecules was studied using radioactive precursors. TGF-beta induced a 3-fold increase of mRNA for PG-S1, collagen I and III in both types of fibroblasts. mRNA for PG-S2 increased only slightly (1.7-fold) in human skin fibroblasts; while no effect was noticed in sclera fibroblasts. The expression of fibromodulin mRNA was not effected in any of the cells investigated. IL-1, PDGF and dexamethasone had no significant effects on the levels of proteoglycan and collagen mRNA, respectively. Synthesis and secretion of PG-S1, -S2 and fibromodulin wa studied by labeling with [3H]-leucine and [35S]-sulfate. Final separation of PG-S1 and -S2 was achieved by hydrophobic interaction chromatography. TGF-beta induced a 3- to 6-fold increase of [3H]- and [35S]-labeled PG-S1; while PG-S2 only increased 1.3- to 1.4-fold in both types of fibroblasts. No effect on synthesis and secretion of immunoprecipitated fibromodulin was noted.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 33. |
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| 34. |
- Andersson-Sköld, Yvonne, et al.
(författare)
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An integrated method for assessing climate-related risks and adaptation alternatives in urban areas
- 2015
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Ingår i: Climate Risk Management. - : Elsevier BV. - 2212-0963. ; 7, s. 31-50
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Tidskriftsartikel (refereegranskat)abstract
- © 2015 The Authors. The urban environment is a complex structure with interlinked social, ecological and technical structures. Global warming is expected to have a broad variety of impacts, which will add to the complexity. Climate changes will force adaptation, to reduce climate-related risks. Adaptation measures can address one aspect at the time, or aim for a holistic approach to avoid maladaptation. This paper presents a systematic, integrated approach for assessing alternatives for reducing the risks of heat waves, flooding and air pollution in urban settings, with the aim of reducing the risk of maladaptation. The study includes strategies covering different spatial scales, and both the current climate situation and the climate predicted under climate change scenarios. The adaptation strategies investigated included increasing vegetation; selecting density, height and colour of buildings; and retreat or resist (defend) against sea-level rise. Their effectiveness was assessed with regard to not only flooding, heat stress and air quality but also with regard to resource use, emissions to air (incl. GHG), soil and water, and people's perceptions and vulnerability. The effectiveness of the strategies were ranked on a common scale (from -3 to 3) in an integrated assessment. Integrated assessments are recommended, as they help identify the most sustainable solutions, but to reduce the risk of maladaptation they require experts from a variety of disciplines. The most generally applicable recommendation, derived from the integrated assessment here, taking into account both expertise from different municipal departments, literature surveys, life cycle assessments and publics perceptions, is to increase the urban greenery, as it contributes to several positive aspects such as heat stress mitigation, air quality improvement, effective storm-water and flood-risk management, and it has several positive social impacts. The most favourable alternative was compact, mid-rise, light coloured building design with large parks/green areas and trees near buildings.
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| 35. |
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| 36. |
- Berglund, A Scott, et al.
(författare)
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Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice. Primary and secondary evaluation for localization of phaeochromocytomas
- 2001
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 249:3, s. 247-251
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the diagnostic value of metaiodobenzylguanidine (MIBG) scintigraphy compared with computed tomography (CT) for the localization of phaeochromocytomas in clinical practice. DESIGN: Retrospective comparison between MIBG scintigrams and CT for localization of phaeochromocytomas in all patients successively examined with MIBG scintigraphy in Malmo from 1984 until January 1997. SETTING: Malmo University Hospital, Sweden. SUBJECTS: Sixty-four patients with clinically suspected phaeochromocytomas. MAIN OUTCOME MEASURES: MIBG scintigrams and CTs classified as positive or negative based on original interpretations (primary evaluation) and in a secondary evaluation by one blinded examiner are assessed through histological confirmation or clinical rule out of phaeochromocytomas. RESULTS: Twenty-five patients had surgically removed phaeochromocytomas. The remaining 39 patients had no proof of phaeochromocytomas. In the secondary evaluation, sensitivity for MIBG scintigraphy was 88% (22/25) and for CT was 100% (25/25). The specificity for MIBG scintigraphy was 89% (35/39) but only 50% for CT (18/36). Two out of a total of six extra-adrenal tumours were amongst the false-negative MIBG scintigrams. CONCLUSIONS: MIBG scintigraphy for the localization of phaeochromocytomas is superior to CT as far as specificity, whereas CT has a higher sensitivity. After biochemical diagnosis, CT will detect most phaeochromocytomas. MIBG scintigraphy can be of value in patients who show inconclusive results with biochemical testing and CT.
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| 37. |
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| 38. |
- Falconer, C, et al.
(författare)
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Changes in paraurethral connective tissue at menopause are counteracted by estrogen
- 1996
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Ingår i: Maturitas. - 0378-5122. ; 24:3, s. 197-204
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study whether the transition to menopause is accompanied by changes in the paraurethral connective tissue and if these changes are modified by estrogen replacement therapy.STUDY DESIGN: Biopsies were obtained from the paraurethral tissue from 34 women; 12 menstruating, 14 postmenopausal without estrogen treatment, and 8 with estrogen treatment. Collagen concentration and collagen extractability by pepsin digestion were measured. Proteoglycan composition and concentration were analysed using Alcian blue. The mRNA levels for collagen I and III, the small proteoglycans (PGS) decorin and biglycan, and the large proteoglycan versican, were estimated.RESULTS: The paraurethral biopsies consisted of fibrous connective tissue, with collagen fibers as dominating structure. Several proteoglycans were identified; versican, heparansulphate proteoglycans, biglycan and decorin. The small proteoglycan decorin represented 85% of all proteoglycans. The collagen concentration was almost doubled in postmenopausal biopsies compared to premenopausal. The collagen fibril organization was also changed with higher cross-linking after menopause whereas the amount and the composition of the proteoglycans were unchanged. The proteoglycan/collagen ratio was significantly decreased. Estrogen replacement therapy resulted in decreased collagen concentration, decreased cross-linking of the collagen and reversal of the PGS/collagen ratio to almost premenopausal level. The therapy resulted in increased levels of mRNA for collagen I and III which suggests that the changes are due to an increased turnover.CONCLUSION: The decrease in estrogen levels at menopause results in a connective tissue with different qualities after menopause. Estrogen replacement therapy tends to restore the metabolism of the genitourinary connective tissue to premenopausal conditions.
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| 39. |
- Falconer, C, et al.
(författare)
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Paraurethral connective tissue in stress-incontinent women after menopause
- 1998
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - 0001-6349. ; 77:1, s. 95-100
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study whether stress urinary incontinence after menopause is correlated to changes in the paraurethral connective tissue ultrastructure and metabolism.METHODS: Transvaginal biopsies were obtained from the paraurethral connective tissue in stress urinary incontinent women after menopause with and without estrogen replacement therapy, and from comparable controls. All the stress-incontinent women underwent urodynamic investigation. In the specimens, collagen concentration, measured as hydroxyproline, and the degree of extractability by pepsin digestion, were quantified. Proteoglycan composition and concentration were analyzed using Alcian Blue precipitation, followed by electro-phoretic separation and quantification. Using Northern blots, mRNA levels for the collagens I and III, the small proteoglycans decorin and biglycan, and the large proteoglycan versican, were quantified. Collagen structure was examined with transmission electron microscopy, and the diameters of collagen fibrils were analyzed with an interactive image analysis system (IBAS, Zeiss/Kontron).RESULTS: No significant difference in paraurethral connective tissue biochemistry or ultrastructure was registered between women with stress incontinence and controls. Estrogen replacement therapy resulted in a lower collagen concentration both between the controls (p = 0.02) and between the incontinent women (0.02). In the women with stress incontinence also the extractability by pepsin digestion was higher in the group with estrogen treatment (p = 0.004), indicating a decrease in cross-linking. The proteoglycan/collagen ratio was higher in the control group with estrogen treatment compared to untreated (p = 0.02), but no difference was found between estrogen treated and untreated incontinent women. The median collagen fibril diameter was 15% larger in the incontinent group of women without estrogen therapy compared to the control group and 5% larger when comparing the incontinent group on estrogen replacement therapy to the corresponding control group.CONCLUSION: The extracellular matrix of paraurethral connective tissue in stress urinary incontinent women after menopause reacted differently to estrogen replacement therapy compared to continent controls. In contrast to incontinent women of fertile age no major changes in collagen metabolism were found in stress urinary incontinent women after menopause.
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| 40. |
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| 41. |
- Forsén, A, et al.
(författare)
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A 14-year prospective study of autonomic nerve function in Type 1 diabetic patients: association with nephropathy.
- 2004
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 21:8, s. 852-858
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Tidskriftsartikel (refereegranskat)abstract
- Aims Prospective studies of autonomic nerve function are rare. We have followed the progression of autonomic dysfunction in relation to nephropathy over 14 years in Type 1 diabetic patients. Methods Autonomic nerve function was assessed by heart-rate responses to deep breathing (E/I ratio) and tilting (acceleration and brake indices) and by the postural blood pressure reaction in 58 patients, 43 of whom were reassessed after 14 years. Nephropathy was evaluated by the degree of albuminuria (albuminuria > 20 µg/min or > 0.03 g/24 h) and glomerular filtration rate (51Cr-EDTA plasma clearance). The acceleration index had deteriorated after 7 years (P = 0.0155), whereas the E/I ratio (P = 0.0070) and the diastolic postural blood pressure reaction (P = 0.0054) had deteriorated 14 years after the baseline examination (age-corrected values). All those with albuminuria at the third examination showed signs of autonomic neuropathy at baseline (10 of 10) compared with only nine of 22 without (P = 0.0016). Multiple regression analysis showed that the association between autonomic dysfunction and future albuminuria was due to the E/I ratio. In addition, individuals with an abnormal postural diastolic blood pressure fall (n = 7) at baseline showed a greater fall in glomerular filtration rate more than others 7-14 years later [29 (16.5) ml/min/1.72 m2 vs. 11 (9) ml/min/1.72 m2; P = 0.0074]. Conclusion Autonomic nerve function had deteriorated after 14 years. Autonomic neuropathy and abnormal postural diastolic blood pressure falls at baseline were associated with future renal complications.
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| 42. |
- Galazka, Martyna A, et al.
(författare)
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Self-reported eye contact sensitivity and face processing in chromosome 22q11.2 deletion syndrome
- 2023
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Ingår i: Journal of Clinical and Experimental Neuropsychology. - 1380-3395 .- 1744-411X. ; 45:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: 22q11.2 deletion syndrome (22qDS) has been associated with varying levels of social impairments, and with atypical visual scanning of faces. The present study explored whether self-reported sensitivity to eye contact might be related to these phenomena. Method: Individuals with confirmed 22qDS were interviewed about their experience and possible discomfort with eye contact. In cases where individuals expresesed discomfort, they were subsequently asked about coping mechanisms used to deal with this discomfort. In addition to self-reported eye contact discomfort, gaze to emotional faces was examined using eye tracking. Results: In the subgroup of individuals who reported discomfort during eye contact, eye tracking results revealed a lower amount of gaze in the eyes of neutral faces, as well as the absence of the typical left visual field (LVF) bias, indicative of alterations in hemispheric lateralization. This subgroup also scored lower on a measure of everyday functioning. Conclusions: Our results show that, by simply asking individuals with this social and communicative disorder about eye gaze discomfort, we may better understand the specific challenges that they experience. Moreover, information gained from such first-person reports together with eye-tracking measures further informs about the integrity of their face processing system, as well as about the nature and degree of impairment in this population.
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| 43. |
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| 44. |
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| 45. |
- Kalkner, Karl Mikael, et al.
(författare)
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Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer
- 2006
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1476-5608 .- 1365-7852. ; 9:1, s. 92-98
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Tidskriftsartikel (refereegranskat)abstract
- In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.
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| 46. |
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| 47. |
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| 48. |
- Peljto, Anna L, et al.
(författare)
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Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants
- 2023
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 207:9, s. 1194-1202
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown.OBJECTIVES: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk.METHODS: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants.MEASUREMENTS AND MAIN RESULTS: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%).CONCLUSIONS: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.
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| 49. |
- Roos, Floris J.M., et al.
(författare)
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Human branching cholangiocyte organoids recapitulate functional bile duct formation
- 2022
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 29:5, s. 13-794
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Tidskriftsartikel (refereegranskat)abstract
- Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids lack the branching morphology of intrahepatic bile ducts (IHBDs). Here, we report establishing human branching cholangiocyte organoid (BRCO) cultures. BRCOs self-organize into complex tubular structures resembling the IHBD architecture. Single-cell transcriptomics and functional analysis showed high similarity to primary cholangiocytes, and importantly, the branching growth mimics aspects of tubular development and is dependent on JAG1/NOTCH2 signaling. When applied to cholangiocarcinoma tumor organoids, the morphology changes to an in vitro morphology like primary tumors. Moreover, these branching cholangiocarcinoma organoids (BRCCAOs) better match the transcriptomic profile of primary tumors and showed increased chemoresistance to gemcitabine and cisplatin. In conclusion, BRCOs recapitulate a complex process of branching morphogenesis in vitro. This provides an improved model to study tubular formation, bile duct functionality, and associated biliary diseases.
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| 50. |
- Söderlund, Z, et al.
(författare)
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Controlled release of growth factors using synthetic glycosaminoglycans in a modular macroporous scaffold for tissue regeneration
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Healthy regeneration of tissue relies on a well-orchestrated release of growth factors. Herein, we show the use of synthetic glycosaminoglycans for controlled binding and release of growth factors to induce a desired cellular response. First, we screened glycosaminoglycans with growth factors of interest to determine kon (association rate constant), koff (dissociation rate constant), and Kd (equilibrium rate constant). As proof-of-concept, we functionalized an elastin-like recombinamer (ELR) hydrogel with a synthetic glycosaminoglycan and immobilized fibroblast growth factor 2 (FGF2), demonstrating that human umbilical vein endothelial cells cultured on top of ELR hydrogel differentiated into tube-like structures. Taking this concept further, we developed a tunable macroporous ELR cryogel material, containing a synthetic glycosaminoglycan and FGF2 that showed increased blood vessel formation and reduced immune response compared to control when implanted in a subcutaneous mouse model. These results demonstrated the possibility for specific release of desired growth factors in/from a modular 3D scaffold in vitro and in vivo.
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