| 1. |
- Cameron, F. J., et al.
(author)
-
Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?
- 2008
-
In: Diabetic Medicine. - : Wiley-Blackwell Publishing Inc.. - 0742-3071 .- 1464-5491. ; 25:4, s. 463-468
-
Journal article (peer-reviewed)abstract
- AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood.RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen.CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres
|
|
| 2. |
- Shah, R, et al.
(author)
-
The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer.
- 2009
-
In: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 100:10, s. 1687-96
-
Journal article (peer-reviewed)abstract
- Expression of P3H2 (Leprel1) and P3H3 (Leprel2) but not P3H1 (Leprecan) is down-regulated in breast cancer by aberrant CpG methylation in the 5' regulatory sequences of each gene. Methylation of P3H2 appears specific to breast cancer as no methylation was detected in a range of cell lines from other epithelial cancers or from primary brain tumours or malignant melanoma. Methylation in P3H2, but not P3H3, was strongly associated with oestrogen-receptor-positive breast cancers, whereas methylation in P3H3 was associated with higher tumour grade and Nottingham Prognostic Index. Ectopic expression of P3H2 and P3H3 in cell lines with silencing of the endogenous gene results in suppression of colony growth. This is the first demonstration of epigenetic inactivation of prolyl hydroxylases in human cancer, implying that this gene family represents a novel class of tumour suppressors. The restriction of silencing in P3H2 to breast carcinomas, and its association with oestrogen-receptor-positive cases, suggests that P3H2 may be a breast-cancer-specific tumour suppressor.
|
|
| 3. |
- Berthold, R., et al.
(author)
-
Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
- 2022
-
In: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 11:1
-
Journal article (peer-reviewed)abstract
- Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1 ' s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.
|
|
| 4. |
- Fioretos, Thoas, et al.
(author)
-
Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia
- 1993
-
In: Leukemia. - 1476-5551. ; 7:8, s. 1225-1231
-
Journal article (peer-reviewed)abstract
- We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.
|
|
| 5. |
- Kaas, A., et al.
(author)
-
Association between age, IL-10, IFN gamma, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes
- 2012
-
In: Diabetic Medicine. - : Wiley-Blackwell. - 0742-3071 .- 1464-5491. ; 29:6, s. 734-741
-
Journal article (peer-reviewed)abstract
- AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes.METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months.RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups.CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.
|
|
| 6. |
- Lingnert, H, et al.
(author)
-
Acrylamide in food: mechanism of formation and influencing factors during heating of foods
- 2002
-
In: Scandinavian Journal of Food and Nutrition. - : Informa UK Limited. - 1748-2976. ; 46:4, s. 159-172
-
Journal article (peer-reviewed)abstract
- Background: In April 2002, the Swedish National Food Administration and a scientific group at the University of Stockholm jointly announced that they had shown acrylamide to be formed during the preparation of food and found it to occur in many foodstuffs. These new findings were clearly of concern to many types of industrial food processing as well as to home cooking. The Swedish Food Federation (Li) initiated and financed the formation of an expert committee to look into the chemical mechanisms. The present review is the final report of that expert committee. Design: The study identified, examined and put together facts and present knowledge on reaction routes for acrylamide formation in food and causal connections to cooking and food processing conditions. The results are based on literature surveys, examination of the analytical data published by the Swedish National Food Administration and other follow-up studies, contacts with international scientific networks, and observations from food companies. Results: The exact chemical mechanism(s) for acrylamide formation in heated foods is unknown. Several plausible mechanistic routes may be suggested, involving reactions of carbohydrates, proteins/amino acids, lipids and probably also other food components as precursors. With the data and knowledge available today it is not possible to point out any specific routes, or to exclude any possibilities. It is likely that a multitude of reaction mechanisms is involved. Acrolein is one strong precursor candidate, the origin of which could be lipids, carbohydrates or proteins/amino acids. Acrylamide is a reactive molecule and it can readily react with various other components in the food. The actual acrylamide level in a specific food product, therefore, probably reflects the balance between ease of formation and potential for further reactions in that food matrix. There are indications in support of that the Maillard reaction being an important reaction route for acrylamide formation, but lipid degradation pathways to the formation of acrolein should also be considered. Conclusions: Reliable analytical methods to measure acrylamide in foods are available. Model studies are needed to identify precursors and reaction route(s) based on current hypotheses and to elucidate possible further reactions between acrylamide and other food components. Studies are needed to optimize formulation and processing conditions to minimize acrylamide levels, taking other product quality properties into consideration.
|
|
| 7. |
- Lodefalk, Maria, 1968-, et al.
(author)
-
Effects of fat supplementation on glycaemic response and gastric emptying in adolescents with Type 1 diabetes
- 2008
-
In: Diabetic Medicine. - Oxford : Blackwell. - 0742-3071 .- 1464-5491. ; 25:9, s. 1030-1035
-
Journal article (peer-reviewed)abstract
- AIMS: To compare the glycaemic response to meals with different fat content in adolescents with Type 1 diabetes mellitus (T1DM) and to investigate associations with gastric emptying.METHODS: In this randomized, cross-over study, paired results were obtained from seven adolescents with T1DM who ingested on different days two meals with the same carbohydrate and protein content, but different fat and energy content (2 and 38 g fat, 320 and 640 kcal, respectively). Paracetamol was mixed into the meals and gastric emptying was estimated by the paracetamol absorption method. All subjects were normoglycaemic and given 7 IU insulin aspart at commencement of ingestion. Postprandial blood samples were taken during 4 h.RESULTS: The areas under the curves for plasma glucose and serum paracetamol concentrations were larger after the low-fat than after the high-fat meal during the first 2 h (P = 0.047 and P = 0.041, respectively). The difference between meals in time-to-peak in glucose and paracetamol concentrations did not reach statistical significance (high-fat vs. low-fat meal: 210 min (120-240) vs. 120 min (50-240), P = 0.080 and 120 min (75-180) vs. 60 min (60-120), P = 0.051, respectively). Changes in glucose concentrations correlated with simultaneous changes in paracetamol concentrations (P < 0.001).CONCLUSIONS: For the first time, we have shown that the initial glycaemic response is reduced after a meal with higher compared with a meal with lower fat content in adolescents with T1DM given a rapid-acting insulin analogue preprandially. The type and dose of preprandial insulin may need adjustment to the fat content of the meal to reach postprandial normoglycaemia.
|
|
| 8. |
- Mutisya, Joel, et al.
(author)
-
Starch branching enzymes in sorghum (Sorghum bicolor) and barley (Hordeum vulgare) : Comparative analyses of enzyme structure and gene expression
- 2003
-
In: Journal of plant physiology (Print). - : Elsevier BV. - 0176-1617 .- 1618-1328. ; 160:8, s. 921-930
-
Journal article (peer-reviewed)abstract
- Summary A genomic clone for starch branching enzyme (SBE) IIb was isolated from a sorghum bacterial artificial chromosome (BAC) library. The promoter and 5′ flanking sequence, the first four exons and introns as well as the last exon and the 3′ untranslated region were sequenced. The tentative transcription start site of sorghum sbeIIb was mapped based on alignment with the maize sbeIIb gene. The exon-intron structure of the 5′ portion of sorghum sbeIIb was similar to that of maize sbeIIb but differed from that of barley sbeIIb. Specifically, the intronic Bbl element involved in the endosperm specific expression of barley sbeIIb was lacking in the sorghum gene. A cDNA clone for sorghum sbeIIb was reverse PCR amplified and found to encode an 803 amino acids long protein. The amino acid sequence of sorghum SBEIIb was compared to that of sorghum SBEI and corresponding enzymes in barley. The overall identity in amino acid sequence was 54 percnt; in the central portion of the enzymes. A major difference between the SBEII and SBEI isoforms was a 67 amino acids-long C-terminal extension in the SBEIs. The spatial and temporal expression patterns of sorghum sbeIIb was determined and compared with those of the sorghum gene for SBEI and the barley genes for SBEIIB and SBEI. All four genes exhibited a seed specific expression. However, while barley sbeIIb and sbeI transcripts were detected exclusively in the endosperm, the sorghum genes were expressed also in the embryo. The activity of sorghum sbeIIb and sbeI exhibited a late onset, with a peak of transcription at around 22 days after pollination. This is similar to the pattern of barley sbeI but different from that of barley sbeIIb, which showed a peak of transcription at 12 days after pollination.
|
|
| 9. |
|
|
| 10. |
- Sievers, E., et al.
(author)
-
SRC inhibition represents a potential therapeutic strategy in liposarcoma
- 2015
-
In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 137:11, s. 2578-2588
-
Journal article (peer-reviewed)abstract
- Liposarcomas (LS) are the most common malignant mesenchymal tumors, with an overall long-term mortality rate of 60%. LS comprise three major subtypes, i.e., well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS), myxoid/round cell liposarcoma (MLS) and pleomorphic liposarcoma (PLS). Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional significance of SRC in primary human LS and in LS-derived cell lines. Immunohistochemical and Western blot analyses reveal relevant levels of activated p-(Tyr416)-SRC in LS of the different subtypes with particular activation in MLS and PLS. Dysregulation of the SRC modifiers CSK and PTP1B was excluded as major reason for the activation of the kinase. Consistent siRNA-mediated knockdown of SRC or inhibition by the SRC inhibitor Dasatinib led to decreased proliferation of LS cell lines of the different subtypes, with MLS cells reacting particularly sensitive in MTT assays. Flow cytometric analyses revealed that this effect was due to a significant decrease in mitotic activity and an induction of apoptosis. SRC inhibition by Dasatinib resulted in dephosphorylation of SRC itself, its interacting partners FAK and IGF-IR as well as its downstream target AKT. Consistent with a particular role of SRC in cell motility, Dasatinib reduced the migratory and invasive potential of MLS cells in Boyden chamber and Matrigel chamber assays. In summary, we provide evidence that SRC activation plays an important role in LS biology and therefore represents a potential therapeutic target, particularly in MLS and PLS.
|
|
