| 1. |
- Sakornsakolpat, Phuwanat, et al.
(author)
-
Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
- 2019
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
-
Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
|
|
| 2. |
- Thorgeirsson, T. E., et al.
(author)
-
A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
- 2016
-
In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:5, s. 594-600
-
Journal article (peer-reviewed)abstract
- Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
|
|
| 3. |
- Bölling, T, et al.
(author)
-
Development of Curative Therapies for Ewing Sarcomas by Interdisciplinary Cooperative Groups in Europe.
- 2015
-
In: Klinische Pädiatrie. - : Georg Thieme Verlag KG. - 1439-3824 .- 0300-8630. ; 227:3, s. 108-115
-
Research review (peer-reviewed)abstract
- Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
|
|
| 4. |
- Peterziel, H, et al.
(author)
-
Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
- 2022
-
In: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1, s. 94-
-
Journal article (peer-reviewed)abstract
- The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
|
|
| 5. |
- Stark, D, et al.
(author)
-
Teenagers and young adults with cancer in Europe: from national programmes to a European integrated coordinated project.
- 2015
-
In: European Journal of Cancer Care. - : Hindawi Limited. - 1365-2354 .- 0961-5423.
-
Journal article (peer-reviewed)abstract
- Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer.
|
|
| 6. |
- de Val-Borro, M., et al.
(author)
-
A comparative study of disc-planet interaction
- 2006
-
In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 370:529, s. 29-
-
Journal article (peer-reviewed)abstract
- We perform numerical simulations of a disc-planet system using various grid-based and smoothed particle hydrodynamics (SPH) codes. The tests are run for a simple setup where Jupiter and Neptune mass planets on a circular orbit open a gap in a protoplanetary disc during a few hundred orbital periods. We compare the surface density contours, potential vorticity and smoothed radial profiles at several times. The disc mass and gravitational torque time evolution are analysed with high temporal resolution. There is overall consistency between the codes. The density profiles agree within about 5 per cent for the Eulerian simulations. The SPH results predict the correct shape of the gap although have less resolution in the low-density regions and weaker planetary wakes. The disc masses after 200 orbital periods agree within 10 per cent. The spread is larger in the tidal torques acting on the planet which agree within a factor of 2 at the end of the simulation. In the Neptune case, the dispersion in the torques is greater than for Jupiter, possibly owing to the contribution from the not completely cleared region close to the planet.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Kersting, J., et al.
(author)
-
Effect of Radiotherapy Dose on Outcome in Nonmetastatic Sarcoma
- 2023
-
In: Advances in Radiation Oncology. ; 8:4
-
Journal article (peer-reviewed)abstract
- Purpose: Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS.Methods and Materials: The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S & RT group) and/or RT (RT group). EFS and OS were analyzed with uni-and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response.Results: S & RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose =53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose > 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S & RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age > 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S & RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40).Conclusions: In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.
|
|
| 10. |
- Mulder, Renée L., et al.
(author)
-
Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer : recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group
- 2021
-
In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 22:2, s. 68-80
-
Research review (peer-reviewed)abstract
- Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.
|
|
