| 1. |
- Bielack, Stefan S, et al.
(författare)
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Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial
- 2015
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 33:20, s. 2279-2287
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Tidskriftsartikel (refereegranskat)abstract
- Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.
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| 2. |
- Gebhardt, Anja J., et al.
(författare)
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Parenting stress and its association with perceived agreement about the disclosure decision in parents following donor conception
- 2017
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 96:8, s. 968-975
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Tidskriftsartikel (refereegranskat)abstract
- Introduction For many donor-conceiving heterosexual parents, the process of deciding whether and what to tell children about their genetic origin is challenging. We hypothesized that incomplete couple agreement about disclosure could be associated with parenting stress. The aim of the study was to investigate: (1) parenting stress levels among heterosexual parents of young children following gamete donation and (2) whether parenting stress is related to perceived agreement about disclosure of the donor conception to the children.Material and methods This study is part of the longitudinal multicenter Swedish Study on Gamete Donation and included a total of 213 heterosexual parents with children aged 1-4years following oocyte donation (n=103) and sperm donation (n=110). Parents individually completed a questionnaire that included validated instruments on parenting stress (SPSQ) and relationship quality (ENRICH), as well as a study-specific measure on disclosure agreement. Multiple regression analysis was applied.Results Incomplete couple agreement on disclosure to the children was not statistically significantly associated with increased levels of parenting stress. Relationship satisfaction consistently and significantly accounted for variation in parenting stress levels, indicating that relationship satisfaction had a buffering impact on parenting stress.Conclusions Parental stress does not appear to be negatively influenced by incomplete couple agreement about disclosure to children. As children grow up, reaching agreement about what to tell the child about the donor conception might become more relevant for couples' stress related to parenthood.
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| 3. |
- Keller, Maria, et al.
(författare)
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Genetically programmed changes in transcription of the novel progranulin regulator
- 2020
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 98:8, s. 1139-1148
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 × 10−7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10−3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P < 1 × 10−7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. Key messages: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels.rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding.PSRC1 is also epigenetically regulated in subjects with high progranulin levels.
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| 4. |
- Miranda, Jezid, et al.
(författare)
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Global health systems strengthening: FIGO's strategic view on reducing maternal and newborn mortality worldwide.
- 2024
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Ingår i: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. - 1879-3479.
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Forskningsöversikt (refereegranskat)abstract
- To demonstrate that successful health systems strengthening (HSS) projects have addressed disparities and inequities in maternal and perinatal care in low-income countries.A comprehensive literature review covered the period between 1980 and 2022, focusing on successful HSS interventions within health systems' seven core components that improved maternal and perinatal care.The findings highlight the importance of integrating quality interventions into robust health systems, as this has been shown to reduce maternal and newborn mortality. However, several challenges, including service delivery gaps, poor data use, and funding deficits, continue to hinder the delivery of quality care. To improve maternal and newborn health outcomes, a comprehensive HSS strategy is essential, which should include infrastructure enhancement, workforce skill development, access to essential medicines, and active community engagement.Effective health systems, leadership, and community engagement are crucial for a comprehensive HSS approach to catalyze progress toward universal health coverage and global improvements in maternal and newborn health.
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| 5. |
- Tönjes, Anke, et al.
(författare)
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Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:3, s. 546-558
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Tidskriftsartikel (refereegranskat)abstract
- Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N=848) and KORA (N=1628) from Germany and PPP-Botnia (N=335) from Finland (total N=2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N=967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N=833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23- PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P=5.75x10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P=1.51x10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.
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