| 1. |
- Andersson, Björn, 1977, et al.
(författare)
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Protein profiling identified dissociations between growth hormone-mediated longitudinal growth and bone mineralization in short prepubertal children
- 2011
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1876-7737 .- 1874-3919. ; 74:1, s. 89-100
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) promotes longitudinal growth and bone mineralization. In this study, a proteomic approach was used to analyze the association between serum protein expression pattern and height-adjusted bone mineralization in short prepubertal children receiving GH treatment. Patterns of protein expression were compared with those associated with longitudinal bone growth. Specific protein expression patterns associated with changes in height-adjusted bone mineralization in response to GH treatment were identified. Out of the 37 peaks found in significant regression models, 27 were uniquely present in models correlated with changes in bone mineralization and 7 peaks were uniquely present in models correlated with changes in height. The peaks identified corresponded to apolipoproteins, transthyretin, serum amyloid A4 and hemoglobin beta. We conclude that a proteomic approach could be used to identify specific protein expression patterns associated with bone mineralization in response to GH treatment and that height-adjusted bone mineralization and longitudinal bone growth are regulated partly by the same and partly by different mechanisms. Protein isoforms with different post-translational modifications might be of importance in the regulation of these processes. However, further validation is needed to assess the clinical significance of the results.
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| 2. |
- Andersson, Björn, 1977, et al.
(författare)
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Proteins related to lipoprotein profile were identified using a pharmaco-proteomic approach as markers for growth response to growth hormone (GH) treatment in short prepubertal children
- 2009
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Ingår i: Proteome Science. - : Springer Science and Business Media LLC. - 1477-5956. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The broad range in growth observed in response to growth hormone (GH) treatment is mainly caused by individual variations in both GH secretion and GH sensitivity. Individual GH responsiveness can be estimated using evidence-based models that predict the response to GH treatment; however, these models can be improved. High-throughput proteomics techniques can be used to identify proteins that may potentially be used as variables in such models in order to improve their predictive ability. Previously we have reported that proteomic analyses can identify biomarkers that discriminate between short prepubertal children with idiopathic short stature (ISS) who show good or poor growth in response to GH treatment. In this study we used a pharmaco-proteomic approach to identify novel factors that correlate with the growth response to GH treatment in prepubertal children who are short due to GH deficiency or ISS. The study included 128 short prepubertal children receiving GH treatment, of whom 39 were GH-deficient and 89 had ISS. Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using SELDI-TOF. Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year growth response to GH treatment. RESULTS: At start of treatment we identified a combination of seven protein peaks that correlated with the 2-year growth response in the GH-deficient group (R2 = 0.73). After 1 year of treatment, a combination of four peaks in the GH-deficient group (R2 = 0.64), eight peaks in the ISS group R2 = 0.47) and eight peaks in the total study group correlated with the 2-year growth response R2 = 0.38).The peaks identified corresponded to apolipoproteins A-I, A-II, C-I, C-III, transthyretin and serum amyloid A 4, which are all part of the high-density lipoprotein. CONCLUSION: Using a proteomic approach we identified biomarkers related to the lipoprotein profile that could be used to predict growth response to GH treatment in prepubertal children who are short as a result of GH-deficiency or who have ISS.These results support our previous findings that apolipoproteins and transthyretin may have a role in GH sensitivity.
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| 3. |
- Cakir, B., et al.
(författare)
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Thrombocytopenia is associated with severe retinopathy of prematurity
- 2018
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Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 3:19
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Tidskriftsartikel (refereegranskat)abstract
- Retinopathy of prematurity (ROP) is characterized by abnormal retinal neovascularization in response to vessel loss. Platelets regulate angiogenesis and may influence ROP progression. In preterm infants, we assessed ROP and correlated with longitudinal postnatal platelet counts (n = 202). Any episode of thrombocytopenia (< 100 x 10(9)/l) at >= 30 weeks postmenstrual age (at onset of ROP) was independently associated with severe ROP, requiring treatment. Infants with severe ROP also had a lower weekly median platelet count compared with infants with less severe ROP. In a mouse oxygen-induced retinopathy model of ROP, platelet counts were lower at P17 (peak neovascularization) versus controls. Platelet transfusions at P15 and P16 suppressed neovascularization, and platelet depletion increased neovascularization. Platelet transfusion decreased retinal of vascular endothelial growth factor A (VEGFA) mRNA and protein expression; platelet depletion increased retinal VEGFA mRNA and protein expression. Resting platelets with intact granules reduced neovascularization, while thrombin-activated degranulated platelets did not. These data suggest that platelet releasate has a local antiangiogenic effect on endothelial cells to exert a downstream suppression of VEGFA in neural retina. Low platelet counts during the neovascularization phase in ROP is significantly associated with the development of severe ROP in preterm infants. In a murine model of retinopathy, platelet transfusion during the period of neovascularization suppressed retinopathy.
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| 4. |
- Decker, Ralph, 1968, et al.
(författare)
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Protein markers of body composition in response to growth hormone (GH) treatment in short prepubertal children
- 2010
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Ingår i: Hormone Research Paediatr.
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Konferensbidrag (refereegranskat)abstract
- Background Recently our group identified lipoprotein biomarkers able to predict linear growth response to GH treatment in short prepubertal children. Previously, it was also shown that biomarkers identified by a proteomic approach were able to discriminate between good or poor growth responders to GH treatment. Hypothesis We hypothesize that high-throughput proteomics techniques can be used to identify proteins not only to predict longitudinal growth response, but also changes in body composition. Objectives The objectives are to implement newly identified biomarkers in future advanced prediction models to avoid over- and under-treatment with GH and to find surrogate markers for predictors difficult to access, e.g. growth hormone (GH) secretion capacity. Study design 128 short prepubertal children were included in the study receiving GH treatment, of whom 39 were GH-deficient and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Body composition after 2 years was analyzed by DEXA. Statistics Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year changes in body composition during GH treatment. Results In the present study we identified biomarkers able to predict lean mass (from arms and legs) and the decrease in subcutaneous fat mass (from arms and legs) at 2 yrs using a pharmaco-proteomic approach. Apolipoproteins were identified as unique markers of the GH treatment on lean mass and of fat mass (r2 >0.32, p<0.05). Serum amyloid A4, belonging to the apolipoprotein family, was a marker of both muscle and fat mass. Conclusion We show a proteomic approach being suitable to identify biomarkers before start of GH treatment playing a role in lipid transport and lipid metabolism able to predict body composition at 1 and 2 years of GH treatment.
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| 5. |
- Decker, Ralph, 1968, et al.
(författare)
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Protein markers predict body composition during growth hormone (GH) treatment in short prepubertal children.
- 2013
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 79:5, s. 675-82
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A high-throughput pharmaco-proteomic approach has previously been successfully used to identify lipoprotein biomarkers related to changes in longitudinal growth and bone mass in response to growth hormone (GH) treatment. The aim of this study was to identify protein markers involved in the diverse anabolic and lipolytic remodelling of body composition during GH treatment. DESIGN, PATIENTS AND MEASUREMENTS: The study population consisted of 128 prepubertal children receiving GH treatment. Thirty-nine were short as a result of GH deficiency and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after one year of GH treatment were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Body composition was analysed by dual-energy X-ray absorptiometry (DXA), reliably estimating muscle mass from appendicular (arms and legs) lean soft tissue mass (LST). DXA was also used to estimate appendicular bone mineral content (BMC) and fat mass for the total body. RESULTS: Specific protein expression patterns associated with GH response in different body compartments were identified. Among identified proteins different isoforms of nutrition markers such as apolipoproteins (Apo) were recognized; Apo C-I, Apo A-II, serum amyloid A4 (SAA4) and transthyretin (TTR). In addition, unidentified peaks were associated with GH effects on specific body compartments. CONCLUSIONS: Our results suggest that unique protein markers are associated with remodelling of different body compartments during GH treatment, which in the future might be useful to optimize GH treatment not only with regard to longitudinal growth. © 2013 Blackwell Publishing Ltd.
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| 6. |
- Hagman, Cecilia, et al.
(författare)
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Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants
- 2018
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Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863. ; 53:10, s. 1399-1406
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundClub cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. AimTo evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. MethodsA study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24h from birth. ResultsCC16 in gastric fluid increased with gestational age (P=0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1 (P=0.028), TNF- (P=0.034), and MMP-9 (P=0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P=0.011 and P=0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO(2) at 6h (P=0.009), higher PaCO2 at 24h (P=0.03), more ventilator days (P=0.012) and more days with supplemental oxygen (P=0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P=0.049). ConclusionA low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24h of life and with more need for respiratory support in the neonatal period.
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| 7. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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A proteomic approach identified growth hormone dependent nutrition markers in children with idiopathic short stature
- 2008
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Ingår i: Proteome Science. - : Springer Science and Business Media LLC. - 1477-5956. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The broad range in growth observed in short prepubertal children receiving the same growth hormone (GH) dose is due to individual variation in GH responsiveness. This study used a pharmaco-proteomic approach in order to identify novel biomarkers that discriminate between short non-GH-deficient (GHD) children who show a good or poor growth response to GH treatment. A group of 32 prepubertal children with idiopathic short stature (ISS) were included in the study. Children were classified on the basis of their first year growth velocity as either good (high responders, n = 13; range, 0.9-1.3 standard deviation score (SDS) or poor (low responders, n = 19; range, 0.3-0.5 SDS) responders to GH treatment (33 microg/kg daily). Serum protein expression profiles before, and after 1 year of GH treatment, were analyzed on a weak cationic exchange array (CM10) using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS: Changes in the intensity of two protein peaks (13.788 kDa and 17.139 kD) during the study period allowed the correct classification of 82% of children as high and low responders, respectively. The 13.788 kD peak, transthyretin, decreased in the high-responder group and increased in the low-responder group during 1 year of GH treatment, whereas the 17.139 kDa peak, apolipoprotein A-II (Apo A-II) decreased in the high-responder group and remained unchanged in the low-responder group. These peaks were identified by the consistency of peak pattern in the spectra, serum depletion experiments using specific antibodies and mass spectrometry. CONCLUSION: Our results suggest that transthyretin and apolipoprotein A-II may have a role in GH sensitivity and could be used as markers to predict which short prepubertal children with ISS will show a good or poor response to GH treatment.
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| 8. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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Construction of a soluble human GH-receptor/EGF-receptor hybrid and its activation by GH
- 2004
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Ingår i: Cytokine. ; 25:6, s. 260-4
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Tidskriftsartikel (refereegranskat)abstract
- To develop a cell-free system that can be used to measure cytokine bioactivity we have designed a soluble hybrid molecule consisting of the extracellular domain of the GH-receptor (GHR) and the intracellular domain of the epidermal growth factor receptor (EGFR). A DNA construct encoding this hybrid-receptor was inserted into a baculoviral expression vector and expressed in Sf9-cells. Activation of the hybrid-receptor by ligand-induced dimerization can be measured as the incorporation of radiolabeled phosphate into a biotinylated tyrosine kinase peptide substrate. The kinase activity in samples stimulated with GH (10 ng/ml) increased 5-fold compared to samples without addition of GH. This is the first example of a functional hybrid-receptor where the transmembrane domain has been deleted. Our results suggest that such hybrid-receptors may be used for detection of GH and other cytokine-receptor activating substances in biological fluids.
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| 9. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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Decreased Platelet Counts and Serum Levels of VEGF-A, PDGF-BB, and BDNF in Extremely Preterm Infants Developing Severe ROP
- 2021
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Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 118, s. 18-27
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. Methods: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. Results: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). Conclusion: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.
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| 10. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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Effect of Preterm Birth on Postnatal Apolipoprotein and Adipocytokine Profiles
- 2015
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Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 108:1, s. 16-22
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Tidskriftsartikel (refereegranskat)abstract
- Background: Critical metabolic changes preparing for ex utero life may occur at the fetal age of approximately 28-32 weeks, and preterm birth <28 weeks postmenstrual age (PMA) may affect these pathways. Children born <28 weeks often have poorer outcomes possibly due to a major shift in metabolism, including nutritional supply and a shift in lipid-transporting particles and lipid profile. This shift may occur in apolipoprotein and adipocytokine levels, which may influence metabolism. Objective: To determine whether there is a shift in apolipoprotein and adipocytokine levels in neonates born at a gestational age (GA) of 28 and 32 weeks, respectively. Methods: Blood samples from 47 infants (GA 32 weeks, n = 30 and GA 28 weeks, n = 17) were collected at birth and, in the GA28 group, also at PMA 32 weeks. Apolipoproteins A-1, A-2, B, C-2, C-3, and E were analyzed, as well as adiponectin and leptin levels. Results: Serum levels of apolipoproteins A-1, C-2, C-3, and E were lower at birth in the GA28 group compared to the GA32 group. Adiponectin and leptin levels were low at birth in the GA28 group. In the GA28 group 4 weeks after birth, leptin levels were still low, whereas adiponectin levels had increased to levels similar to those found at birth in the GA32 group. Apolipoprotein A-1, C-2, C-3, and E levels were negatively correlated with days receiving total parenteral nutrition. Conclusion: There are significant differences in apolipoprotein and adipocytokine levels, which can be associated with GA and birth weight. The impact of these changes on neonatal and future morbidity remains to be determined. (C) 2015 S. Karger AG, Basel
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