| 1. |
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| 2. |
- Parker, C., et al.
(author)
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Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer
- 2013
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 369:3, s. 213-223
-
Journal article (peer-reviewed)abstract
- Background Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. Methods In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. Results At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. Conclusions In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.)
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| 3. |
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| 4. |
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| 5. |
- Anderson, Beverley H., et al.
(author)
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Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 338-342
-
Journal article (peer-reviewed)abstract
- Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous gamma H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the alpha-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-alpha primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Ruffini, M, et al.
(author)
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DISCUS : The Distributed Core For Ubiquitous Broadband Access
- 2013
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In: Future Network and MobileSummit 2013.
-
Conference paper (peer-reviewed)abstract
- A new end to end architecture based on Long-Reach Passive OpticalNetwork (LR-PON) with wireless integration, a distributed core built of opticaltransparency islands and an OpenFlow-based control plane, which is beingdeveloped in the EU project DISCUS, is described in this paper. The maintechnological advances and the network modelling and optimization approach arereported.
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| 10. |
- Salvo, P., et al.
(author)
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Fabrication and functionalization of PCB gold electrodes suitable for DNA-based electrochemical sensing
- 2014
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In: Bio-medical materials and engineering. - 0959-2989 .- 1878-3619. ; 24:4, s. 1705-1714
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Journal article (peer-reviewed)abstract
- The request of high specificity and selectivity sensors suitable for mass production is a constant demand in medical research. For applications in point-of-care diagnostics and therapy, there is a high demand for low cost and rapid sensing platforms. This paper describes the fabrication and functionalization of gold electrodes arrays for the detection of deoxyribonucleic acid (DNA) in printed circuit board (PCB) technology. The process can be implemented to produce efficiently a large number of biosensors. We report an electrolytic plating procedure to fabricate low-density gold microarrays on PCB suitable for electrochemical DNA detection in research fields such as cancer diagnostics or pharmacogenetics, where biosensors are usually targeted to detect a small number of genes. PCB technology allows producing high precision, fast and low cost microelectrodes. The surface of the microarray is functionalized with self-assembled monolayers of mercaptoundodecanoic acid or thiolated DNA. The PCB microarray is tested by cyclic voltammetry in presence of 5 mM of the redox probe K3Fe(CN6) in 0.1 M KCl. The voltammograms prove the correct immobilization of both the alkanethiol systems. The sensor is tested for detecting relevant markers for breast cancer. Results for 5 nM of the target TACSTD1 against the complementary TACSTD1 and non-complementary GRP, MYC, SCGB2A1, SCGB2A2, TOP2A probes show a remarkable detection limit of 0.05 nM and a high specificity.
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| 11. |
- Wang, Thomas J., et al.
(author)
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2-Aminoadipic acid is a biomarker for diabetes risk
- 2013
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In: Journal of Clinical Investigation. - 0021-9738. ; 123:10, s. 4309-4317
-
Journal article (peer-reviewed)abstract
- Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic beta cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
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| 12. |
- Wheal, Amanda J., et al.
(author)
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Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation
- 2014
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 351:2, s. 457-466
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Journal article (peer-reviewed)abstract
- Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 mu M) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator-activated receptor-gamma antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide-, and hydrogen peroxide-independent. It was, however, COX-1/2- and superoxide dismutase-dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E-2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F-1 alpha was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors.
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| 13. |
- Agrawal, Vikas, et al.
(author)
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The AAAI-13 Conference Workshops
- 2013
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In: The AI Magazine. - : Association for the Advancement of Artificial Intelligence. - 0738-4602 .- 2371-9621. ; 34:4, s. 108-115
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Journal article (peer-reviewed)abstract
- The AAAI-13 Workshop Program, a part of the 27th AAAI Conference on Artificial Intelligence, was held Sunday and Monday, July 14-15, 2013, at the Hyatt Regency Bellevue Hotel in Bellevue, Washington, USA. The program included 12 workshops covering a wide range of topics in artificial intelligence, including Activity Context-Aware System Architectures (WS-13-05); Artificial Intelligence and Robotics Methods in Computational Biology (WS-13-06); Combining Constraint Solving with Mining and Learning (WS-13-07); Computer Poker and Imperfect Information (WS-13-08); Expanding the Boundaries of Health Informatics Using Artificial Intelligence (WS-13-09); Intelligent Robotic Systems (WS-13-10); Intelligent Techniques for Web Personalization and Recommendation (WS-13-11); Learning Rich Representations from Low-Level Sensors (WS-13-12); Plan, Activity,, and Intent Recognition (WS-13-13); Space, Time, and Ambient Intelligence (WS-13-14); Trading Agent Design and Analysis (WS-13-15); and Statistical Relational Artificial Intelligence (WS-13-16)
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| 14. |
- Di Giglio, A., et al.
(author)
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Towards the distributed core for ubiquitous superfast broadband optical access
- 2014
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In: 2014 European Conference on Networks and Communications (EuCNC). ; , s. 1-5
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Conference paper (peer-reviewed)abstract
- In this paper, we describe recent architectural and technological advances of the end to end optical network architecture proposed by the DISCUS project (the DIStributed Core for unlimited bandwidth supply for all Users and Services). The two main targets of DISCUS are the principle of equivalence in the access and the reduction of optical-to-electronic conversions in the metro-core network. Technological advances and techno-economic evaluation of Long-Reach Passive Optical Networks (LR-PON), as well as the optimal metro-core node architecture and the required network control plane framework are reported. Network infrastructure sharing challenges are also discussed.
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| 15. |
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| 16. |
- Karlsson, Jenny, et al.
(author)
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Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin.
- 2014
-
In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 53:5, s. 381-391
-
Journal article (peer-reviewed)abstract
- Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state. © 2014 Wiley Periodicals, Inc.
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| 17. |
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| 18. |
- Lindgren, Hanna, et al.
(author)
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Putaminal Upregulation of FosB/Delta FosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
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In: Journal of Parkinson's Disease. - 1877-718X. ; 1:4, s. 347-357
-
Journal article (peer-reviewed)abstract
- The transcription factor Delta FosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and Delta FosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/Delta FosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/Delta FosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/Delta FosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/Delta FosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of Delta FosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
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| 19. |
- Lindgren, Hanna S., et al.
(author)
-
Putaminal Upregulation of FosB/ΔFosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
-
In: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 1:4, s. 347-357
-
Journal article (peer-reviewed)abstract
- The transcription factor FosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson´s disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and FosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/ FosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ FosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/ FosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/ FosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of FosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
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| 20. |
- Maher, Ann Butler, et al.
(author)
-
Acute nursing care of the older adult with fragility hip fracture : An international perspective (Part 2)
- 2013
-
In: International Journal of Orthopaedic and Trauma Nursing. - : Elsevier. - 1878-1241 .- 1878-1292. ; 17:1, s. 4-18
-
Journal article (peer-reviewed)abstract
- The second part of this paper provides those who care for orthopaedic patients with evidence-supported international perspectives about acute nursing care of the older adult with fragility hip fracture. Developed by an international group of nurse experts and guided by a range of information from research and clinical practice, it focuses on nurse sensitive quality indicators during the acute hospitalisation for fragility hip fracture. Optimal care for the patient who has experienced such a fracture is the focus. This includes (in the first, earlier, part):PainDeliriumand in this partPressure UlcersFluid Balance/NutritionConstipation/Catheter Associated Urinary Tract InfectionVigilant nursing assessment and prompt intervention may prevent the development of the complications we discuss. If they do occur and are identified early on, they may resolve with appropriate and timely nursing management.This “tool kit” has been developed under the auspices of the International Collaboration of Orthopaedic Nursing (ICON) a coalition of national associations of orthopaedic nursing (www.orthopaedicnursing.org).
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| 21. |
- Maher, Ann Butler, et al.
(author)
-
Acute nursing care of the older adult with fragility hip fracture : An international perspective (Part 1)
- 2012
-
In: International Journal of Orthopaedic and Trauma Nursing. - : Elsevier. - 1878-1241 .- 1878-1292. ; 16:4, s. 177-194
-
Journal article (peer-reviewed)abstract
- This paper provides those who care for orthopaedic patients with evidence-supported international perspectives about acute nursing care of the older adult with fragility hip fracture. Developed by an international group of nurse experts and guided by a range of information from research and clinical practice, it focuses on nurse sensitive quality indicators during the acute hospitalisation for fragility hip fracture. Optimal care for the patient who has experienced such a fracture is the focus here. This includes in this part:PainDeliriumand in the second, subsequent, partPressure UlcersFluid Balance/NutritionConstipation/Catheter Associated Urinary Tract InfectionVigilant nursing assessment and prompt intervention may prevent the development of the complications we discuss. If they do occur and are identified early on, they may resolve with appropriate and timely nursing management.This “tool kit” has been developed under the auspices of the International Collaboration of Orthopaedic Nursing (ICON) a coalition of national associations of orthopaedic nursing (www.orthopaedicnursing.org).Previous article in issue
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| 22. |
- Ohlin, Elisabet, et al.
(author)
-
Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.
- 2011
-
In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 134, s. 2339-2357
-
Journal article (peer-reviewed)abstract
- Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
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| 23. |
- O'Meara, Elaine, et al.
(author)
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Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney
- 2012
-
In: Journal of Pathology. - : Wiley. - 0022-3417. ; 227:1, s. 72-80
-
Journal article (peer-reviewed)abstract
- Clear cell sarcoma of kidney (CCSK) is classified as a tumour of unfavourable histology by the National Wilms' Tumor Study Group. It has worse clinical outcomes than Wilms' tumour. Virtually nothing is known about CCSK biology, as there have been very few genetic aberrations identified to act as pointers in this cancer. Three cases of CCSK bearing a chromosomal translocation, t(10;17)(q22;p13), have been individually reported but not further investigated to date. The aim of this research was to characterize t(10;17)(q22;p13) in CCSK to identify the genes involved in the translocation breakpoints. Using fluorescently labelled bacterial artificial chromosomes (BACs) and a chromosome-walking strategy on an index case of CCSK with t(10;17)(q22;p13) by karyotype, we identified the chromosomal breakpoints on 17p13.3 and 10q22.3. The translocation results in rearrangement of YWHAE on chromosome 17 and FAM22 on chromosome 10, producing an in-frame fusion transcript of similar to 3 kb, incorporating exons 15 of YWHAE and exons 2-7 of FAM22, as determined by RT-PCR using YWHAE- and FAM22-specific primers. The YWHAE-FAM22 transcript was detected in six of 50 further CCSKs tested, therefore showing an overall incidence of 12% in our cohort. No transcript-positive cases presented with stage I disease, despite this being the stage for 31% of our cohort. Tumour cellularity was significantly higher in the cases that were transcript-positive. Based on the chromosome 10 breakpoint identified by FISH and the sequences of the full-length transcripts obtained, the FAM22 members involved in the translocation in these CCSK cases include FAM22B and FAM22E. Elucidation of the role of YWHAE-FAM22 in CCSK will assist development of more efficient and targeted therapies for this childhood cancer, which currently has poor outcomes. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 24. |
- Ruffini, M., et al.
(author)
-
DISCUS : An End-to-End Solution for Ubiquitous Broadband Optical Access
- 2014
-
In: IEEE Communications Magazine. - 0163-6804 .- 1558-1896. ; 52:2, s. S24-S32
-
Journal article (peer-reviewed)abstract
- Fiber to the premises has promised to increase the capacity in telecommunications access networks for well over 30 years. While it is widely recognized that optical-fiber-based access networks will be a necessity in the shortto medium-term future, its large upfront cost and regulatory issues are pushing many operators to further postpone its deployment, while installing intermediate unambitious solutions such as fiber to the cabinet. Such high investment cost of both network access and core capacity upgrade often derives from poor planning strategies that do not consider the necessity to adequately modify the network architecture to fully exploit the cost benefit that a fiber-centric solution can bring. DISCUS is a European Framework 7 Integrated Project that, building on optical-centric solutions such as long-reach passive optical access and flat optical core, aims to deliver a cost-effective architecture for ubiquitous broadband services. DISCUS analyzes, designs, and demonstrates end-to-end architectures and technologies capable of saving cost and energy by reducing the number of electronic terminations in the network and sharing the deployment costs among a larger number of users compared to current fiber access systems. This article describes the network architecture and the supporting technologies behind DISCUS, giving an overview of the concepts and methodologies that will be used to deliver our end-to-end network solution.
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| 25. |
- Rylander, Daniella, et al.
(author)
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Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia.
- 2010
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:5, s. 619-628
-
Journal article (peer-reviewed)abstract
- OBJECTIVE:: Striatal serotonin projections have been implicated in levodopa-induced dyskinesia by providing an unregulated source of dopamine release. We set out to determine whether these projections are affected by levodopa treatment in a way that would favor the occurrence of dyskinesia. METHODS:: As an index of terminal serotonin innervation density, we measured radioligand binding to the plasma membrane serotonin transporter (SERT) in levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from both rat and monkey models of Parkinson disease as well as parkinsonian patients. In addition, striatal tissue from dyskinetic rats was used for morphological and ultrastructural analyses of serotonin axon terminals, and for studies of stimulated [(3)H]dopamine release. RESULTS:: Across all conditions examined, striatal levels of SERT radioligand binding were significantly elevated in dyskinetic subjects compared to nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had induced sprouting of serotonin axon varicosities having a relatively high synaptic incidence. This response was associated with increased depolarization-induced [(3)H]dopamine release and with a stronger release potentiation by brain-derived neurotrophic factor. INTERPRETATION:: This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease. Ann Neurol 2010.
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| 26. |
- Sartor, Oliver, et al.
(author)
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Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases : results from a phase 3, double-blind, randomised trial
- 2014
-
In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 15:7, s. 738-746
-
Journal article (peer-reviewed)abstract
- Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range a-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2: 1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15.6 months [95% CI 13.5-18.0] vs 9.8 months [7.3-23.7]; hazard ratio [HR] = 0.66, 95% CI 0.52-0.83; p = 0.00037). The risks of external beam radiation therapy for bone pain (HR 0.67, 95% CI 0.53-0.85) and spinal cord compression (HR = 0.52, 95% CI 0.29-0.93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0.62, 95% CI 0.35-1.09), or the need for tumour-related orthopaedic surgical intervention (HR 0.72, 95% CI 0.28-1.82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.
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| 27. |
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