| 1. |
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| 2. |
- Sampson, Joshua N., et al.
(author)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 3. |
- Enkovaara, J., et al.
(author)
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Electronic structure calculations with GPAW : a real-space implementation of the projector augmented-wave method
- 2010
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In: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 22:25, s. 253202-
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Research review (peer-reviewed)abstract
- Electronic structure calculations have become an indispensable tool in many areas of materials science and quantum chemistry. Even though the Kohn-Sham formulation of the density-functional theory (DFT) simplifies the many-body problem significantly, one is still confronted with several numerical challenges. In this article we present the projector augmented-wave (PAW) method as implemented in the GPAW program package (https://wiki.fysik.dtu.dk/gpaw) using a uniform real-space grid representation of the electronic wavefunctions. Compared to more traditional plane wave or localized basis set approaches, real-space grids offer several advantages, most notably good computational scalability and systematic convergence properties. However, as a unique feature GPAW also facilitates a localized atomic-orbital basis set in addition to the grid. The efficient atomic basis set is complementary to the more accurate grid, and the possibility to seamlessly switch between the two representations provides great flexibility. While DFT allows one to study ground state properties, time-dependent density-functional theory (TDDFT) provides access to the excited states. We have implemented the two common formulations of TDDFT, namely the linear-response and the time propagation schemes. Electron transport calculations under finite-bias conditions can be performed with GPAW using non-equilibrium Green functions and the localized basis set. In addition to the basic features of the real-space PAW method, we also describe the implementation of selected exchange-correlation functionals, parallelization schemes, Delta SCF-method, x-ray absorption spectra, and maximally localized Wannier orbitals.
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| 4. |
- Tran, Thao Thanh, et al.
(author)
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Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages
- 2022
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In: PLoS Pathogens. - : Public Library Science. - 1553-7366 .- 1553-7374. ; 18:1
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Journal article (peer-reviewed)abstract
- A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.
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| 5. |
- Bousquet, Jean, et al.
(author)
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ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
- 2021
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In: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
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Research review (peer-reviewed)abstract
- Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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| 6. |
- Buckland, G., et al.
(author)
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Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:10, s. 2504-2511
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Journal article (peer-reviewed)abstract
- There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers. What's new? Urothelial cell carcinoma (UCC) is the most common form of bladder cancer. Previous studies suggested that plasma carotenoids, antioxidants found in fruit and vegetables, were associated with a decreased risk of UCC while a high intake of animal protein was associated with an increased cancer risk. Here, the authors conducted the first study to investigate the association between the Mediterranean diet, a diet rich in fresh fruits and vegetables and low in animal products, and UCC in Europe. They found that adherence to a Mediterranean diet was not significantly associated with UCC, regardless of level of tumour aggressiveness. They point out that these findings are in line with the rather weak evidence for questionnaire-based associations between dietary factors and bladder cancer risk.
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| 7. |
- Dewaraja, Y K, et al.
(author)
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Accurate dosimetry in I-131 radionuclide therapy using patient-specific, 3-dimensional methods for SPECT reconstruction and absorbed dose calculation
- 2005
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In: Journal of Nuclear Medicine. - 0161-5505. ; 46:5, s. 840-849
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Journal article (peer-reviewed)abstract
- I-131 radionuclide therapy studies have not shown a strong relationship between tumor absorbed dose and response, possibly due to inaccuracies in activity quantification and dose estimation. The goal of this work was to establish the accuracy of I-131 activity quantification and absorbed dose estimation when patient-specific, 3-dimensional (3D) methods are used for SPECT reconstruction and for absorbed dose calculation. Methods: Clinically realistic voxel-phantom simulations were used in the evaluation of activity quantification and dosimetry. SPECT reconstruction was performed using an ordered-subsets expectation maximization (OSEM) algorithm with compensation for scatter, attenuation, and 3D detector response. Based on the SPECT image and a patient-specific density map derived from CT, 3D dosimetry was performed using a newly implemented Monte Carlo code. Dosimetry was evaluated by comparing mean absorbed dose estimates calculated directly from the defined phantom activity map with those calculated from the SPECT image of the phantom. Finally, the 3D methods were applied to a radioimmunotherapy patient, and the mean tumor absorbed dose from the new calculation was compared with that from conventional dosimetry obtained from conjugate-view imaging. Results: Overall, the accuracy of the SPECT-based absorbed dose estimates in the phantom was > 12% for targets down to 16 mL and up to 35% for the smallest 7-mL tumor. To improve accuracy in the smallest tumor, more OSEM iterations may be needed. The relative SD from multiple realizations was < 3% for all targets except for the smallest tumor. For the patient, the mean tumor absorbed dose estimate from the new Monte Carlo calculation was 7% higher than that from conventional dosimetry. Conclusion: For target sizes down to 16 mL, highly accurate and precise dosimetry can be obtained with 3D methods for SPECT reconstruction and absorbed dose estimation. In the future, these methods can be applied to patients to potentially establish correlations between tumor regression and the absorbed dose statistics from 3D dosimetry.
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| 8. |
- Gaziano, Liam, et al.
(author)
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Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
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In: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
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Journal article (peer-reviewed)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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| 9. |
- Såmark-Roth, A., et al.
(author)
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Low-lying states in 219Ra and 215Rn : Sampling microsecond α-decaying nuclei
- 2018
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In: Physical Review C. - 2469-9985. ; 98:4
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Journal article (peer-reviewed)abstract
- Short-lived α-decaying nuclei "northeast" of 208Pb in the chart of nuclides were studied using the reaction 48Ca+243Am with the decay station TASISpec at TASCA, GSI Darmstadt. Decay energies and times from pile-up events were extracted with a tailor-made pulse-shape analysis routine and specific α-decay chains were identified in a correlation analysis. Decay chains starting with the even-even 220Ra and its odd-A neighbors, 219Fr, and 219,221Ra, with a focus on the 219Ra→215Rn decay, were studied by means of α-γ spectroscopy. A revised α-decay scheme of 219Ra is proposed, including a new decay branch from a previously not considered isomeric state at 17 keV excitation energy. Conclusions on nuclear structure are drawn from the experimental data, aided by Geant4 simulations and a discussion on theoretical calculations.
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| 10. |
- Wang, Zhaoming, et al.
(author)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 11. |
- Bahi, R., et al.
(author)
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Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency
- 2015
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In: Progrès en urologie (Paris). - : Elsevier BV. - 1166-7087. ; 25:1, s. 27-33
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Journal article (peer-reviewed)abstract
- Objective: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney.Patients and methods: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk.Results: Mean tumor size was 4.0 ± 2.3 cm and mean pre-operative glomerular filtration rate was 60.8 ± 18.9 mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P = 0.44) nor warm ischemia time (P = 0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P < 0.0001) and blood loss volume (P = 0.02) were significant independent predictive factors of long-term renal failure.Conclusion: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Dewaraja, Y K, et al.
(author)
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Accuracy of 131I tumor quantification in radioimmunotherapy using SPECT imaging with an ultra-high-energy collimator: Monte Carlo study
- 2000
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In: Journal of Nuclear Medicine. - 0161-5505. ; 41:10, s. 1760-1760
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Journal article (peer-reviewed)abstract
- Accuracy of 131I tumor quantification after radioimmunotherapy (RIT) was investigated for SPECT imaging with an ultra-high-energy (UHE) collimator designed for imaging 511-keV photons. METHODS: First, measurements and Monte Carlo simulations were carried out to compare the UHE collimator with a conventionally used, high-energy collimator. On the basis of this comparison, the UHE collimator was selected for this investigation, which was carried out by simulation of spherical tumors in a phantom. Reconstruction was by an expectation-maximization algorithm that included scatter and attenuation correction. Keeping the tumor activity constant, simulations were carried out to assess how volume-of-interest (VOI) counts vary with background activity, radius of rotation (ROR), tumor location, and size. The constant calibration factor for quantification was determined from VOI counts corresponding to a 3.63-cm-radius sphere of known activity. Tight VOIs corresponding to the physical size of the spheres or tumors were used. RESULTS: Use of the UHE collimator resulted in a large reduction in 131I penetration, which is especially significant in RIT where background uptake is high. With the UHE collimator, typical patient images showed an improvement in contrast. Considering the desired geometric events, sensitivity was reduced, but only by a factor of 1.6. Simulation results for a 3.63-cm-radius tumor showed that VOI counts vary with background, location, and ROR by less than 3.2%, 3%, and 5.3%, respectively. The variation with tumor size was more significant and was a function of the background. Good quantification accuracy (<6.5% error) was achieved when tumor size was the same as the sphere size used in the calibration, irrespective of the other parameters. For smaller tumors, activities were underestimated by up to -15% for the 2.88-cm-radius sphere, -23% for the 2.29-cm-radius sphere, and -47% for the 1.68-cm-radius sphere. CONCLUSION: Reasonable accuracy can be achieved for VOI quantification of 131I using SPECT with an UHE collimator and a constant calibration factor. Difference in tumor size relative to the size of the calibration sphere had the biggest effect on accuracy, and recovery coefficients are needed to improve quantification of small tumors.
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| 16. |
- Dewaraja, Y K, et al.
(author)
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Characterization of scatter and penetration using Monte Carlo simulation in 131I imaging
- 2000
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In: Journal of Nuclear Medicine. - 0161-5505. ; 41:1, s. 123-130
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Journal article (peer-reviewed)abstract
- In 131I SPECT, image quality and quantification accuracy are degraded by object scatter as well as scatter and penetration in the collimator. The characterization of energy and spatial distributions of scatter and penetration performed in this study by Monte Carlo simulation will be useful for the development and evaluation of techniques that compensate for such events in 131I imaging. METHODS: First, to test the accuracy of the Monte Carlo model, simulated and measured data were compared for both a point source and a phantom. Next, simulations to investigate scatter and penetration were performed for four geometries: point source in air, point source in a water-filled cylinder, hot sphere in a cylinder filled with nonradioactive water, and hot sphere in a cylinder filled with radioactive water. Energy spectra were separated according to order of scatter, type of interaction, and gamma-ray emission energy. A preliminary evaluation of the triple-energy window (TEW) scatter correction method was performed. RESULTS: The accuracy of the Monte Carlo model was verified by the good agreement between measured and simulated energy spectra and radial point spread functions. For a point source in air, simulations show that 73% of events in the photopeak window had either scattered in or penetrated the collimator, indicating the significance of collimator interactions. For a point source in a water-filled phantom, the separated energy spectra showed that a 20% photopeak window can be used to eliminate events that scatter more than two times in the phantom. For the hot sphere phantoms, it was shown that in the photopeak region the spectrum shape of penetration events is very similar to that of primary (no scatter and no penetration) events. For the hot sphere regions of interest, the percentage difference between true scatter counts and the TEW estimate of scatter counts was <12%. CONCLUSION: In 131I SPECT, object scatter as well as collimator scatter and penetration are significant. The TEW method provides a reasonable correction for scatter, but the similarity between the 364-keV primary and penetration energy spectra makes it difficult to compensate for these penetration events using techniques that are based on spectral analysis.
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| 17. |
- Dewaraja, Yuni K., et al.
(author)
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Improved quantitative 90Y bremsstrahlung SPECT/CT reconstruction with Monte Carlo scatter modeling
- 2017
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In: Medical Physics. - : Wiley. - 0094-2405. ; 44:12, s. 6364-6376
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Journal article (peer-reviewed)abstract
- Purpose: In 90Y microsphere radioembolization (RE), accurate post-therapy imaging-based dosimetry is important for establishing absorbed dose versus outcome relationships for developing future treatment planning strategies. Additionally, accurately assessing microsphere distributions is important because of concerns for unexpected activity deposition outside the liver. Quantitative 90Y imaging by either SPECT or PET is challenging. In 90Y SPECT model based methods are necessary for scatter correction because energy window-based methods are not feasible with the continuous bremsstrahlung energy spectrum. The objective of this work was to implement and evaluate a scatter estimation method for accurate 90Y bremsstrahlung SPECT/CT imaging. Methods: Since a fully Monte Carlo (MC) approach to 90Y SPECT reconstruction is computationally very demanding, in the present study the scatter estimate generated by a MC simulator was combined with an analytical projector in the 3D OS-EM reconstruction model. A single window (105 to 195-keV) was used for both the acquisition and the projector modeling. A liver/lung torso phantom with intrahepatic lesions and low-uptake extrahepatic objects was imaged to evaluate SPECT/CT reconstruction without and with scatter correction. Clinical application was demonstrated by applying the reconstruction approach to five patients treated with RE to determine lesion and normal liver activity concentrations using a (liver) relative calibration. Results: There was convergence of the scatter estimate after just two updates, greatly reducing computational requirements. In the phantom study, compared with reconstruction without scatter correction, with MC scatter modeling there was substantial improvement in activity recovery in intrahepatic lesions (from > 55% to > 86%), normal liver (from 113% to 104%), and lungs (from 227% to 104%) with only a small degradation in noise (13% vs. 17%). Similarly, with scatter modeling contrast improved substantially both visually and in terms of a detectability index, which was especially relevant for the low uptake extrahepatic objects. The trends observed for the phantom were also seen in the patient studies where lesion activity concentrations and lesion-to-liver concentration ratios were lower for SPECT without scatter correction compared with reconstruction with just two MC scatter updates: in eleven lesions the mean uptake was 4.9 vs. 7.1 MBq/mL (P = 0.0547), the mean normal liver uptake was 1.6 vs. 1.5 MBq/mL (P = 0.056) and the mean lesion-to-liver uptake ratio was 2.7 vs. 4.3 (P = 0.0402) for reconstruction without and with scatter correction respectively. Conclusions: Quantitative accuracy of 90Y bremsstrahlung imaging can be substantially improved with MC scatter modeling without significant degradation in image noise or intensive computational requirements.
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| 18. |
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| 19. |
- Figueroa, Jonine D., et al.
(author)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Journal article (peer-reviewed)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 20. |
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| 21. |
- Hinkula, Jorma, et al.
(author)
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HIVIS-DNA or HIVISopt-DNA priming followed by CMDR vaccinia-based boosts induce both humoral and cellular murine immune responses to HIV.
- 2017
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In: Heliyon. - : Elsevier. - 2405-8440. ; 3:6
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Journal article (peer-reviewed)abstract
- BACKGROUND: In order to develop a more effective prophylactic HIV-1 vaccine it is important optimize the components, improve Envelope glycoprotein immunogenicity as well as to explore prime-boost immunization schedules. It is also valuable to include several HIV-1 subtype antigens representing the world-wide epidemic.METHODS: HIVIS-DNA plasmids which include Env genes of subtypes A, B and C together with Gag subtypes A and B and RTmut/Rev of subtype B were modified as follows: the Envelope sequences were shortened, codon optimized, provided with an FT4 sequence and an immunodominant region mutated. The reverse transcriptase (RT) gene was shortened to contain the most immunogenic N-terminal fragment and fused with an inactivated viral protease vPR gene. HIVISopt-DNA thus contains fewer plasmids but additional PR epitopes compared to the native HIVIS-DNA. DNA components were delivered intradermally to young Balb/c mice once, using a needle-free Biojector® immediately followed by dermal electroporation. Vaccinia-based MVA-CMDR boosts including Env gene E and Gag-RT genes A were delivered intramuscularly by needle, once or twice.RESULTS: Both HIVIS-DNA and HIVISopt-DNA primed humoral and cell mediated responses well. When boosted with heterologous MVA-CMDR (subtypes A and E) virus inhibitory neutralizing antibodies were obtained to HIV-1 subtypes A, B, C and AE. Both plasmid compositions boosted with MVA-CMDR generated HIV-1 specific cellular responses directed against HIV-1 Env, Gag and Pol, as measured by IFNγ ELISpot. It was shown that DNA priming augmented the vector MVA immunological boosting effects, the HIVISopt-DNA with a trend to improved (Env) neutralization, the HIVIS-DNA with a trend to better (Gag) cell mediated immune reponses.CONCLUSIONS: HIVIS-DNA was modified to obtain HIVISopt-DNA that had fewer plasmids, and additional epitopes. Even with one DNA prime followed by two MVA-CMDR boosts, humoral and cell-mediated immune responses were readily induced by priming with either DNA construct composition. Priming by HIV-DNA augmented neutralizing antibody responses revealed by boosting with the vaccinia-based heterologous sequences. Cellular and antibody responses covered selected strains representing HIV-1 subtypes A, B, C and CRF01_AE. We assume this is related to the inclusion of heterologous full genes in the vaccine schedule.
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| 23. |
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| 24. |
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| 25. |
- Pignot, G., et al.
(author)
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L’Ischémie n’est pas un facteur d’insuffisance rénale chronique après néphrectomie partielle sur rein unique
- 2014
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In: Progrès en urologie (Paris). - : Elsevier. - 1166-7087. ; 24:13, s. 822-822
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Journal article (peer-reviewed)abstract
- Objectifs Déterminer l‘influence du clampage pédiculaire et de sa durée sur la fonction rénale à long terme après néphrectomie partielle (NP) pour cancer sur rein unique.Méthodes L’étude a inclus rétrospectivement 259 patients opérés par NP entre 1979 et 2010 dans 13 centres. L’utilisation d’un clampage, son type (pédiculaire ou parenchymateux), sa durée ainsi que les données pré-, intra- et postopératoires ont été recueillies. Les valeurs de débit de filtration glomérulaire (DFG) préopératoire et au dernier suivi ont été comparés. Une analyse multivariée selon le modèle de Cox a été réalisée afin de déterminer l’impact de l’ischémie sur le risque d’insuffisance rénale (IR) chronique postopératoire.Résultats La taille moyenne des tumeurs était de 4,0±2,3cm et le DFG préopératoire moyen de 60,8±18,9ml/min. Au total, 106 patients ont été opérés en ischémie chaude (40,9 %) et 53 en ischémie froide (20,5 %). Trente patients (11,6 %) ont évolué vers l’insuffisance rénale chronique. En analyse multivariée, ni le clampage pédiculaire (p=0,44), ni la durée d’ischémie chaude (p=0,1) n’étaient associés à une évolution vers l’insuffisance rénale. Les facteurs indépendants d’insuffisance rénale à long terme étaient le DFG préopératoire (p<0,0001) et les pertes sanguines (p=0,02).Conclusion La fonction rénale après NP sur rein unique apparaît principalement liée à des facteurs non modifiables et notamment le DFG préopératoire. Ce travail relativise l’importance du clampage pédiculaire et du temps d’ischémie qui n’étaient pas significativement liés au risque d’IR dans notre étude.
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