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| 2. |
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| 3. |
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| 4. |
- Adam, A, et al.
(författare)
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Abstracts from Hydrocephalus 2016.
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 7. |
- Smith Byrne, K., et al.
(författare)
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The role of plasma microseminoprotein-beta in prostate cancer : An observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 30:6, s. 983-989
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Tidskriftsartikel (refereegranskat)abstract
- Background: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. Patients and methods: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. Results: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. Conclusions: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.
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| 8. |
- Lilja, Gisela, et al.
(författare)
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Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest A Predefined Analysis of the TTM2 Randomized Clinical Trial
- 2023
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Ingår i: Jama Neurology. - 2168-6149 .- 2168-6157. ; 80:10, s. 1070-1079
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. OBJECTIVES To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. DESIGN, SETTING, AND PARTICIPANTS This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. INTERVENTIONS Randomization 1:1 to temperature control with targeted hypothermia at 33 degrees C or targeted normothermia and early treatment of fever (37.8 degrees C or higher). MAIN OUTCOMES AND MEASURES Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. RESULTS At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P =.46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P =.37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P =.62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). CONCLUSIONS In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common.
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| 9. |
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| 10. |
- Stenman, U H, et al.
(författare)
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Summary report of the TD-3 workshop: characterization of 83 antibodies against prostate-specific antigen
- 1999
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 20:Suppl. 1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Twelve research groups participated in the ISOBM TD-3 Workshop in which the reactivity and specificity of 83 antibodies against prostate-specific antigen (PSA) were investigated. Using a variety of techniques including cross-inhibition assays, Western blotting, BIAcore, immunoradiometric assays and immunohistochemistry, the antibodies were categorized into six major groups which formed the basis for mapping onto two- and three-dimensional (2-D and 3-D) models of PSA. The overall findings of the TD-3 Workshop are summarized in this report. In agreement with all participating groups, three main antigenic domains were identified: free PSA-specific epitopes located in or close to amino acids 86-91; discontinuous epitopes specific for PSA without human kallikrein (hK2) cross-reactivity located at or close to amino acids 158-163; and continuous or linear epitopes shared between PSA and hK2 located close to amino acids 3-11. In addition, several minor and partly overlapping domains were also identified. Clearly, the characterization of antibodies from this workshop and the location of their epitopes on the 3-D model of PSA illustrate the importance of selecting appropriate antibody pairs for use in immunoassays. It is hoped that these findings and the epitope nomenclature described in this TD-3 Workshop are used as a standard for future evaluation of anti-PSA antibodies.
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| 11. |
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| 12. |
- Gehlen, J., et al.
(författare)
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First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
- 2022
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Ingår i: Human Genetics and Genomics Advances. - : Elsevier BV. - 2666-2477. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes. © 2022 The Authors
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| 13. |
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| 14. |
- Semb, G, et al.
(författare)
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Erratum
- 2017
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Ingår i: Journal of plastic surgery and hand surgery. - 2000-6764. ; 51:2, s. 158-158
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Tidskriftsartikel (refereegranskat)
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| 15. |
- Thal, D. R., et al.
(författare)
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Different aspects of Alzheimer's disease-related amyloid beta-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia
- 2019
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD)-related amyloid beta-peptide (A beta) pathology in the form of amyloid plaques and cerebral amyloid angiopathy (CAA) spreads in its topographical distribution, increases in quantity, and undergoes qualitative changes in its composition of modified A beta species throughout the pathogenesis of AD. It is not clear which of these aspects of A beta pathology contribute to AD progression and to what extent amyloid positron emission tomography (PET) reflects each of these aspects. To address these questions three cohorts of human autopsy cases (in total n = 271) were neuropathologically and biochemically examined for the topographical distribution of A beta pathology (plaques and CAA), its quantity and its composition. These parameters were compared with neurofibrillary tangle (NFT) and neuritic plaque pathology, the degree of dementia and the results from [F-18]flutemetamol amyloid PET imaging in cohort 3. All three aspects of A beta pathology correlated with one another, the estimation of A beta pathology by [F-18]flutemetamol PET, AD-related NFT pathology, neuritic plaques, and with the degree of dementia. These results show that one aspect of A beta pathology can be used to predict the other two, and correlates well with the development of dementia, advancing NFT and neuritic plaque pathology. Moreover, amyloid PET estimates all three aspects of A beta pathology in-vivo. Accordingly, amyloid PET-based estimates for staging of amyloid pathology indicate the progression status of amyloid pathology in general and, in doing so, also of AD pathology. Only 7.75% of our cases deviated from this general association.
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| 16. |
- Adler, Jan-Olof, et al.
(författare)
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The upgraded photon tagging facility at the MAX IV Laboratory
- 2013
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 715, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- A description is given of the upgraded photon tagging facility at the MAX IV Laboratory. Two magnetic spectrometers are used to momentum analyze post-bremsstrahlung electrons. The tagged photon range extends from 10 to 180 MeV with an energy resolution of about 300 keV. The system has been operated at rates up to 4 x 10(6) photons s(-1) MeV (-1). Different diagnostic tools are described as well as the experimental program.
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| 17. |
- Dankiewicz, Josef, et al.
(författare)
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Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
- 2021
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294
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Tidskriftsartikel (refereegranskat)abstract
- Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
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| 18. |
- Denmeade, Samuel R., et al.
(författare)
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Activation of latent protease function of pro-hK2, but not pro-PSA, involves autoprocessing
- 2001
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Ingår i: The Prostate. - : Wiley. - 0270-4137. ; 48:2, s. 122-126
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human glandular kallikrein 2 (hK2) and prostate-specific antigen (PSA) are members of an extensive kallikrein family of proteases. Both proteases are secreted as zymogens or proenzymes containing a seven amino acid propeptide that must be proteolytically removed for enzymatic activation. The physiological proteases that activate pro-hK2 and pro-PSA are not known. METHODS: The pro-hK2 peptide sequence is Val-Pro-Leu-Ile-Gln-Ser-Arg (VPLIQSR). For PSA, the amino acid sequence of the propeptide is Ala-Pro-Leu-Ile-Leu-Ser-Arg (APLILSR). Fluorescent substrates were made by coupling these peptide sequences to 7-amino-4-methylcoumarin (AMC). The hydrolysis of the VPLIQSR-AMC and APLILSR-AMC substrates by hK2, PSA, and a panel of purified proteases was determined. RESULTS: HK2 readily cleaved the pro-hK2 peptide substrate VPLIQSR-AMC with a rate of hydrolysis that was approximately 8-fold higher than an equimolar amount of purified trypsin. HK2 also had the highest hydrolysis rate from among a group of other trypsin-like proteases. In contrast, neither hK2 nor PSA was able to appreciably cleave the pro-PSA substrate APLILSR-AMC. The pro-PSA substrate was most readily hydrolyzed by urokinase and trypsin. CONCLUSIONS: HK2 can hydrolyze the pro-hK2 substrate suggesting that maturation of pro-hK2 to enzymatically active hK2 involves autoprocessing. As expected, PSA, a chymotrypsin-like protease, was unable to hydrolyze either of the propeptide substrates. Therefore, it is unlikely that PSA can auto-process its own enzymatic function. HK2 has trypsin-like specificity but was unable to hydrolyze the pro-PSA substrate. These results raise the possibility that an additional processing protease may be required to fully process PSA to an enzymatically active form.
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| 19. |
- Fielding, R. A., et al.
(författare)
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Effect of structured physical activity and nutritional supplementation on physical function in mobility-limited older adults : Results from the VIVE2 randomized trial
- 2017
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Ingår i: The Journal of Nutrition, Health & Aging. - : Springer Science and Business Media LLC. - 1279-7707 .- 1760-4788. ; 21:9, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. Mobility-limited (Short Physical Performance Battery (SPPB) ae9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. Primary outcome was gait speed assessed by the 400M walk. Results: 149 subjects were randomized into the study (mean age=77.5 +/- 5.4; female=46.3%; mean SPPB= 7.9 +/- 1.2; mean 25(OH)D=18.7 +/- 6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.
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| 20. |
- Hoffmann, Thomas J., et al.
(författare)
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Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.
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| 21. |
- Karlsson, Martin, et al.
(författare)
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Measurement of the differential cross section for the two-body photodisintegration of He-3 at theta(LAB)=90 degrees using tagged photons in the energy range 14-31 MeV
- 2009
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:4
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Tidskriftsartikel (refereegranskat)abstract
- The two-body photodisintegration of He-3 has been investigated using tagged photons with energies from 14-31 MeV at MAX-lab in Lund, Sweden. The two-body breakup channel was unambiguously identified by the (nonsimultaneous) detection of both protons and deuterons. This approach was made feasible by the overdetermined kinematic situation afforded by the tagged-photon technique. Proton-and deuteron-energy spectra were measured using four silicon surface-barrier detector telescopes located at a laboratory angle of 90 degrees with respect to the incident photon-beam direction. Average statistical and systematic uncertainties of 5.7% and 6.6% in the differential cross section were obtained for 11 photon-energy bins with an average width of 1.2 MeV. The results are compared to previous experimental data measured at comparable photon energies as well as to the results of two recent Faddeev calculations which employ realistic potential models and take into account three-nucleon forces and final-state interactions. Both the accuracy and precision of the present data are improved over those obtained in the previous measurements. The data are in good agreement with most of the previous results, and favor the inclusion of three-nucleon forces in the calculations.
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| 22. |
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| 23. |
- Ma, C. R., et al.
(författare)
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Addition of a Genetic Risk Score for Identification of Men with a Low Prostate-specific Antigen Level in Midlife at Risk of Developing Lethal Prostate Cancer
- 2023
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Ingår i: European Urology Open Science. - : Elsevier BV. - 2666-1691 .- 2666-1683. ; 50, s. 27-30
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Tidskriftsartikel (refereegranskat)abstract
- Men with a low prostate-specific antigen (PSA) level (<1 ng/ml) in midlife may extend the rescreening interval (if aged 40-59 yr) or forgo future PSA screening (if aged >60 yr) owing to their low risk of aggressive prostate cancer (PCa). However, there is a subset of men who develop lethal PCa despite low baseline PSA. We investigated how a PCa polygenic risk score (PRS) in addition to baseline PSA impacts the prediction of lethal PCa among 483 men aged 40-70 yr from the Physicians' Health Study followed over a median of 33 yr. We examined the association of the PRS with the risk of lethal PCa (lethal cases vs controls) using logistic regression adjusted for baseline PSA. The PCa PRS was associated with risk of lethal PCa (odds ratio per 1 standard deviation in PRS [OR] 1.79, 95% confidence interval [CI] 1.28-2.49). The association between the PRS and lethal PCa was stronger for those with PSA <1 ng/ml (OR 2.23, 95% CI 1.19-4.21) than for men with PSA >= 1 ng/ml (OR 1.61, 95% CI 1.07-2.42). Our PCa PRS improved the identification of men with PSA <1 ng/ml at greater risk of future lethal PCa who should consider ongoing PSA testing. Patient summary: A subset of men develop fatal prostate cancer despite having low prostate-specific antigen (PSA) levels in middle age. A risk score based on multiple genes can help in predicting men who may be at risk of developing lethal prostate cancer and who should be advised to have regular PSA measurements. (c) 2023 The Authors.
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| 24. |
- McDevitt, Michael R., et al.
(författare)
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Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
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| 25. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 26. |
- Nilsson, C. L., et al.
(författare)
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Chromosome 19 Annotations with Disease Speciation: A First Report from the Global Research Consortium
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:1, s. 134-149
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Tidskriftsartikel (refereegranskat)abstract
- A first research development progress report of the Chromosome 19 Consortium with members from Sweden, Norway, Spain, United States, China and India, a part of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is presented (http://www.c-hpp.org). From the chromosome 19 peptide-targeted library constituting 6159 peptides, a pilot study was conducted using a subset with 125 isotope-labeled peptides. We applied an annotation strategy with triple quadrupole, ESI-Qtrap, and MALDI mass spectrometry platforms, comparing the quality of data within and in between these instrumental set-ups. LC–MS conditions were outlined by multiplex assay developments, followed by MRM assay developments. SRM was applied to biobank samples, quantifying kallikrein 3 (prostate specific antigen) in plasma from prostate cancer patients. The antibody production has been initiated for more than 1200 genes from the entire chromosome 19, and the progress developments are presented. We developed a dedicated transcript microarray to serve as the mRNA identifier by screening cancer cell lines. NAPPA protein arrays were built to align with the transcript data with the Chromosome 19 NAPPA chip, dedicated to 90 proteins, as the first development delivery. We have introduced an IT-infrastructure utilizing a LIMS system that serves as the key interface for the research teams to share and explore data generated within the project. The cross-site data repository will form the basis for sample processing, including biological samples as well as patient samples from national Biobanks.
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| 27. |
- Simpson, Rupert F.G., et al.
(författare)
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Speed of cooling after cardiac arrest in relation to the intervention effect : a sub-study from the TTM2-trial
- 2022
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535 .- 1466-609X. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4–6 on modified Rankin scale). Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84–1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80–1.26). Conclusions: Using a hospital’s average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.
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| 28. |
- Storey, Claire M, et al.
(författare)
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Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response
- 2023
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Ingår i: Molecular cancer research : MCR. - 1557-3125. ; 21:4, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Non-invasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer (PCa) therapies. AR is a critical driver and mediator of resistance of PCa but currently available non-invasive PCa biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of PCa, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied if [&sup89;Zr]11B6-PET can accurately assess EBRT-induced AR activity. Genetic and human PCa mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue. EBRT increased AR pathway activity and [&sup89;Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [&sup89;Zr]11B6 uptake in PCa-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels. Implications: hK2 expression in PCa tissue is a proxy of EBRT-induced AR activity that can non-invasively be detected using [&sup89;Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.
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| 29. |
- Thurfjell, Lennart, et al.
(författare)
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Automated Quantification of F-18-Flutemetamol PET Activity for Categorizing Scans as Negative or Positive for Brain Amyloid: Concordance with Visual Image Reads
- 2014
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X .- 1535-5667. ; 55:10, s. 1623-1628
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Tidskriftsartikel (refereegranskat)abstract
- Clinical trials of the PET amyloid imaging agent F-18-flutemetamol have used visual assessment to classify PET scans as negative or positive for brain amyloid. However, quantification provides additional information about regional and global tracer uptake and may have utility for image assessment over time and across different centers. Using postmortem brain neuritic plaque density data as a truth standard to derive a standardized uptake value ratio (SUVR) threshold, we assessed a fully automated quantification method comparing visual and quantitative scan categorizations. We also compared the histopathology-derived SUVR threshold with one derived from healthy controls. Methods: Data from 345 consenting subjects enrolled in 8 prior clinical trials of F-18-flutemetamol injection were used. We grouped subjects into 3 cohorts: an autopsy cohort (n = 68) comprising terminally ill patients with postmortem confirmation of brain amyloid status; a test cohort (n = 172) comprising 33 patients with clinically probable Alzheimer disease, 80 patients with mild cognitive impairment, and 59 healthy volunteers; and a healthy cohort of 105 volunteers, used to define a reference range for SUVR. Visual image categorizations for comparison were from a previous study. A fully automated PET-only quantification method was used to compute regional neocortical SUVRs that were combined into a single composite SUVR. An SUVR threshold for classifying scans as positive or negative was derived by ranking the PET scans from the autopsy cohort based on their composite SUVR and comparing data with the standard of truth based on postmortem brain amyloid status for subjects in the autopsy cohort. The derived threshold was used to categorize the 172 scans in the test cohort as negative or positive, and results were compared with categorization using visual assessment. Different reference and composite region definitions were assessed. Threshold levels were also compared with corresponding thresholds derived from the healthy group. Results: Automated quantification (using pons as the reference region) demonstrated 91% sensitivity and 88% specificity and gave 3 false-positive and 4 false-negative scans. All 3 false-positive cases were either borderline-normal by standard of truth or had moderate to heavy cortical diffuse plaque burden. In the test cohort, the concordance between quantitative and visual read categorization ranged from 97.1% to 99.4% depending on the selection of reference and composite regions. The threshold derived from the healthy group was close to the histopathology-derived threshold. Conclusion: Categorization of F-18-flutemetamol amyloid imaging data using an automated PET-only quantification method showed good agreement with histopathologic classification of neuritic plaque density and a strong concordance with visual read results.
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| 30. |
- Veach, Darren R., et al.
(författare)
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PSA-Targeted Alpha-, Beta-, and Positron-emitting immunotheranostics in murine prostate cancer models and nonhuman primates
- 2021
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 27:7, s. 2050-2060
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3). Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3-Hi- Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
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| 31. |
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| 32. |
- Wu, X. N., et al.
(författare)
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Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy
- 2019
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Ingår i: Prostate. - : Wiley. - 0270-4137. ; 79:10, s. 1079-1089
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Tidskriftsartikel (refereegranskat)abstract
- Background Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance. Methods EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and gamma H2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition. Results While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased gamma H2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls. Conclusions Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance.
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| 33. |
- Assel, Melissa J., et al.
(författare)
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Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men
- 2019
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Ingår i: Prostate. - : Wiley. - 0270-4137.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood—total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)—or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease. Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes. Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival. Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting.
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| 34. |
- Bicak, Mesude, et al.
(författare)
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Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 117:26, s. 15172-15181
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Tidskriftsartikel (refereegranskat)abstract
- Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
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| 35. |
- Blennow Nordström, Erik, et al.
(författare)
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Combined use of the Montreal Cognitive Assessment and Symbol Digit Modalities Test improves neurocognitive screening accuracy after cardiac arrest : A validation sub-study of the TTM2 trial
- 2024
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Ingår i: Resuscitation. - 0300-9572. ; 202
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To assess the merit of clinical assessment tools in a neurocognitive screening following out-of-hospital cardiac arrest (OHCA).Methods: The neurocognitive screening that was evaluated included the performance-based Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT), the patient-reported Two Simple Questions (TSQ) and the observer-reported Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE-CA). These instruments were administered at 6-months in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. We used a comprehensive neuropsychological test battery from a TTM2 trial sub-study as a gold standard to evaluate the sensitivity and specificity of the neurocognitive screening.Results: In our cohort of 108 OHCA survivors (median age = 62, 88% male), the most favourable cut-off scores were: MoCA < 26; SDMT z ≤ -1; IQCODE-CA ≥ 3.04. The MoCA (sensitivity 0.64, specificity 0.85) and SDMT (sensitivity 0.59, specificity 0.83) had a higher classification accuracy than the TSQ (sensitivity 0.28, specificity 0.74) and IQCODE-CA (sensitivity 0.42, specificity 0.60). When using the cut-points for MoCA or SDMT in combination to identify neurocognitive impairment, sensitivity improved (0.81, specificity 0.74), area under the curve = 0.77, 95% CI [0.69, 0.85]. The most common unidentified impairments were within the episodic memory and executive functions domains, with fewer false negative cases on the MoCA or SDMT combined.Conclusion: The MoCA and SDMT have acceptable diagnostic accuracy for screening for neurocognitive impairment in an OHCA population, and when used in combination the sensitivity improves. Patient and observer-reports correspond poorly with neurocognitive performance.ClinicalTrials.gov Identifier: NCT03543371.
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| 36. |
- Blennow Nordström, Erik, et al.
(författare)
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Neuropsychological outcome after cardiac arrest : results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial
- 2023
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Ingår i: Critical Care. - : BioMed Central (BMC). - 1364-8535 .- 1466-609X. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA.METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes.RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance.CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue.TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.
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| 37. |
- Boström, Peter J, et al.
(författare)
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Genomic Predictors of Outcome in Prostate Cancer.
- 2015
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 68:6, s. 1033-1044
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Forskningsöversikt (refereegranskat)abstract
- Given the highly variable behavior and clinical course of prostate cancer (PCa) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making.
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| 38. |
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| 39. |
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| 40. |
- Bylund, Jonas R
(författare)
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Planning, Projects, Practice : A Human Geography of the Stockholm Local Investment Programme in Hammarby Sjöstad
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Programmes and policies to support ecological sustainable development and the practice of implementation is a question of innovation rather than known and taken for granted procedure. This thesis argues a priori models concerning stability in the social sciences, and human geography especially, are less able to help us understand this practice and planning in such unstable situations. Problematic in common understandings of planning and policy implementation concerning sustainability are the dualisms between physical-social spaces and between rationality-contingency. The first dualism makes it hard to grasp the interaction between humans and nonhumans. The second dualism concerns the problem of how to capture change without resorting to reductionism and explanaining the evolving projects as either technically, economically, or culturally rational. The scope of the thesis is to test resources from actor-network theory as a means of resolving these dualisms. The case is the Stockholm Local Investment Programme and the new district of Hammarby Sjöstad. The programme’s objective was to support the implemention of new technologies and systems, energy efficiency and reduced resource-use as well as eco-cycling measures. The case-study follows how the work with the programme unfolded and how administrators’ efforts to reach satisfactory results was approached. In doing this, the actors had to be far more creative than models of implementation and traditional technology diffusion seem to suggest. The recommendation is to take the instrumentalisation framing the plasticity of a project in planning seriously – as innovativeness is not a special but the general case. Hence, to broaden our tools and understanding of planning a human geography of planning projects is pertinent.
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| 41. |
- Cardinale, Daniele A., et al.
(författare)
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Resistance Training with Co-ingestion of Anti-inflammatory Drugs Attenuates Mitochondrial Function
- 2017
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The current study aimed to examine the effects of resistance exercise with concomitant consumption of high versus low daily doses of non-steroidal anti-inflammatory drugs (NSAIDs) on mitochondrial oxidative phosphorylation in skeletal muscle. As a secondary aim, we compared the effects of eccentric-overload with conventional training. Methods: Twenty participants were randomized to either a group taking high doses (3 x 400 mg/day) of ibuprofen (IBU; 27±5 yr; n=11) or a group ingesting a low dose (1 x 75 mg/day) of acetylsalicylic acid (ASA; 26±4 yr; n=9) during 8 weeks of supervised knee extensor resistance training. Each of the subject’s legs were randomized to complete the training program using either a flywheel (FW) device emphasizing eccentric-overload, or a traditional weight stack machine (WS). Maximal mitochondrial oxidative phosphorylation (CI+IIP) from permeabilized skeletal muscle bundles was assessed using high-resolution respirometry. Citrate synthase (CS) activity was assessed using spectrophotometric techniques and mitochondrial protein content using western blotting. Results: After training, CI+IIP decreased (P<0.05) in both IBU (23%) and ASA (29%) with no difference across medical treatments. Although CI+IIP decreased in both legs, the decrease was greater (interaction p = 0.015) in WS (33%, p = 0.001) compared with FW (19%, p = 0.078). CS activity increased (p = 0.027) with resistance training, with no interactions with medical treatment or training modality. Protein expression of ULK1 increased with training in both groups (p < 0.001). The increase in quadriceps muscle volume was not correlated with changes in CI+IIP (R=0.16). Conclusion: These results suggest that 8 weeks of resistance training with co-ingestion of anti-inflammatory drugs reduces mitochondrial function but increases mitochondrial content. The observed changes were not affected by higher doses of NSAIDs consumption, suggesting that the resistance training intervention was the prime mediator of the decreased mitochondrial phosphorylation. Finally, we noted that flywheel resistance training, emphasizing eccentric overload, rescued some of the reduction in mitochondrial function seen with conventional resistance training.
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| 42. |
- Cardinale, Daniele, et al.
(författare)
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Resistance Exercise Attenuates Mitochondrial Function : Effects Of NSAID Intake And Eccentric-Overload Training
- 2017
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Ingår i: Medicine & Science in Sports & Exercise. 49(5S):329, MAY 2017. - : Ovid Technologies (Wolters Kluwer Health). ; , s. 329-329
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Konferensbidrag (refereegranskat)abstract
- Although nonsteroidal antiinflammatorydrugs (NSAIDs) have been shown to modulate skeletal muscle adaptations and protein metabolism in response toresistance exercise, little is known about the effects of NSAIDs on mitochondrial function. Thus, the current study aimed to examine the effects of resistanceexercise with concomitant NSAID consumption on mitochondrial oxidative phosphorylation in skeletal muscle. Twenty participants were randomized in asingleblindedfashion to either an experimental group receiving ibuprofen (IBU: 27±5 yr; n=11; 1200 mg/d) or a control group receiving a lowdoseacetylsalicylic acid (CON: 26±4 yr; n=9; 75 mg/d) During this period, subjects performed 8 weeks of supervised resistance exercise involving the kneeextensors muscles. Each of the subject’s legs were randomized to complete the training program using either a flywheel (FW) device emphasizing eccentricoverload,or a traditional weight stack machine (WS). Maximal mitochondrial oxidative phosphorylation (OXPHOS) from permeabilized skeletal muscle bundleswas assessed using high resolution respirometry before and after the training intervention. Citrate synthase activity was assessed using spectrophotometrictechniques. After training, OXPHOS decreased (P<0.05) in both IBU (23%) and CON (29%) with no difference across medical treatments. Although OXPHOSdecreased in both legs, the decrease was greater (interaction P= 0.015) in WS (33%, P= 0.015) than in FW (19%, P= 0.078). Citrate synthase (CS) did notchange after the intervention. The increase in quadriceps muscle volume was not significantly correlated with the change in OXPHOS (R=0.15). These resultssuggest that 1) eight weeks of resistance training reduces mitochondrial function but not mitochondrial content, 2) The decreased mitochondrial function withresistance exercise was not affected by ibuprofen consumption, 3) flywheel resistance training, emphasizing eccentric overload, rescues some of thereduction in mitochondrial function seen with conventional resistance training.
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| 43. |
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| 44. |
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| 45. |
- Chen, Dorothy M, et al.
(författare)
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Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
-
Ingår i: Human Genetics and Genomics Advances. - 2666-2477.
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Tidskriftsartikel (refereegranskat)abstract
- Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10 -6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10 -6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10 -6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.
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| 46. |
- Chen, Dorothy M, et al.
(författare)
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Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6 , and RP11-327J17.2 . Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.
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| 47. |
- Chou, Alisha, et al.
(författare)
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Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population : Stability over Time and Comparison with Polygenic Risk Score
- 2022
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 31:12, s. 2199-2207
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer (PCa) development that may help to risk-stratify men earlier in life.METHODS: We examined PSA levels in men measured up to 10+ years before a PCa diagnosis in association with PCa risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for PCa.RESULTS: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a PCa OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared to men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 vs. 8+ disease. At 10+ years, the association of PCa with PSA was comparable to that with the PRS (OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively).CONCLUSIONS: We found PSA to be an informative marker of PCa risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable to a PRS when measured 10+ years before diagnosis.IMPACT: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in PCa screening practices.
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| 48. |
- Cremers, Ruben G., et al.
(författare)
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The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer, early-onset gene mutation carriers
- 2015
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Ingår i: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 33:5, s. 19-202
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. Materials and methods: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level≥3.0. ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate biopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. Results: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff≥25; 34%) or 134 (cutoff≥35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥25; 28%) or 109 (≥35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff≥25) or 43 (cutoff≥35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. Conclusions: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.
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- Danila, DC, et al.
(författare)
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Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:23, s. 7053-7058
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.
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