| 701. |
- Carlsson, Martin, et al.
(författare)
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Erythrocyte fatty acid composition does not influence levels of free, bioavailable, and total 25-hydroxy vitamin D
- 2017
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 77:1, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- In vitro, mono- and polyunsaturated fatty acids (FAs) may decrease the binding affinity of vitamin D metabolites for vitamin D-binding protein, which in turn may influence their bioavailability. FAs incorporated as phospholipids in erythrocyte (ery-) cell membranes reflect dietary intake. The purpose of this study was to investigate ery-FA composition in relation to markers for vitamin D. In healthy females (age 22.6 +/- 2.0 years) total 25(OH)D was measured by LC-MS/MS (n=78), free 25(OH)D with ELISA (n=64 of 78), and bioavailable 25(OH)D was calculated. Analysis of ery-FA composition was by gas chromatography (n=56 of 78). A strong correlation between total 25(OH)D and free 25(OH)D was seen (r=.66, p<.001), and between total-25(OH)D and bioavailable 25(OH)D (r=.68, p<.001). No correlations between 25(OH)D fractions and specific fatty acids were found, and in particular, no associations with mono- and poly-unsaturated FA compositions. All 25(OH)D fractions were correlated with leptin (total 25(OH)D (r=-.33, p<.003); bioavailable 25(OH)D (r=-.47, p<.001); free 25(OH)D (r=-.44, p<.001). Associations were found between PTH and total 25(OH)D (r=-.35, p=.002) and weaker between bioavailable 25(OH)D (r=-.35, p=.040) and free 25(OH)D (r=-.28, p=.079). All fractions of 25(OH)D appear to correlate in a similar way to PTH, BMI and body fat (leptin). No association was found between ery-FA composition and free/bioavailable 25(OH)D. It is unlikely that FAs are a strong uncoupling factor of DBP-bound 25(OH)D.
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| 702. |
- Carlsson, Sofia, et al.
(författare)
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Dependence on Vitamin K-dependent Protein S for Eukaryotic Cell Secretion of the β-Chain of C4b-binding Protein
- 2010
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Ingår i: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 285:42, s. 32038-32046
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Tidskriftsartikel (refereegranskat)abstract
- The anticoagulant vitamin K-dependent protein S (PS) circulates in plasma in two forms, 30% free and 70% being bound to the complement regulatory protein C4b-binding protein (C4BP). The major C4BP isoform consists of 7 α-chains and 1 β-chain (C4BPβ+), the chains being linked by disulfide bridges. PS binds to the β-chain with high affinity. In plasma, PS is in molar excess over C4BPβ+ and due to the high affinity, all C4BPβ+ molecules contain a bound PS. Taken together with the observation that PS-deficient patients have decreased levels of C4BPβ+, this raises the question of whether PS is important for secretion of the β-chain from the cell. To test this hypothesis, HEK293 cells were stably and transiently transfected with β-chain cDNA in combinations with cDNAs for PS and/or the α-chain. The concentration of β-chains in the medium increased after co-transfection with PS cDNA, but not by α-chain cDNA, suggesting secretion of the β-chains from the cells to be dependent on concomitant synthesis of PS, but not of the α-chains. Thus, β-chains that were not disulfide-linked to the α-chains were secreted in complex with PS, either as monomers or dimers. Pulse-chase demonstrated that the complexes between PS and β-chain were formed intracellularly, in the endoplasmic reticulum. In conclusion, our results demonstrate that successful secretion of β-chains depends on intracellular complex formation with PS, but not on the α-chains. This provides an explanation for the decreased β-chain levels observed in PS-deficient patients.
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| 703. |
- Casar-Borota, Olivera, et al.
(författare)
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KIT protein expression and mutational status of KIT gene in pituitary adenomas
- 2012
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Ingår i: Virchows Archiv. - New York : Springer-Verlag New York. - 0945-6317 .- 1432-2307. ; 460:2, s. 171-181
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Tidskriftsartikel (refereegranskat)abstract
- KIT protein expression and mutational status of KIT gene in different types of tumours have been intensively studied since Imatinib Mesylate, KIT/PDGFRA tyrosine kinase inhibitor became available. However, only one immunohistochemical study on KIT expression in pituitary adenomas has been published. There are currently no reports on mutational status of KIT gene in pituitary adenomas. We have immunohistochemically investigated KIT expression in 252 pituitary adenomas and found cytoplasmic reactivity in 52.4% and membranous reactivity in 8.3% of all adenomas. There was statistically significant difference in KIT expression between clinically non-functioning, growth hormone- and adrenocorticotroph hormone-producing adenomas. The group with membranous expression was dominated by somatotropinomas and clinically non-functioning adenomas. KIT expression in a subset of adenomas was also confirmed by western blot analysis of 48 adenomas. Immunohistochemical KIT expression was correlated with basic clinical data and in a cohort of acromegalic patients with additional data (somatostatin receptor type 2A expression, response to somatostatin analogue treatment and mutational status of gsp oncogene). Exons 9, 11, 13 and 17 of KIT gene were searched for mutations in the tumours with membranous KIT expression and in a minority of tumours with cytoplasmic KIT expression using denaturing high-performance liquid chromatography and in suspected cases sequencing of one or more exons. No mutations in the examined exons were found. Our results may suggest a role of KIT in the pathogenesis of a subset of pituitary adenomas and point out the need for further research to find out if KIT-reactive adenomas could be sensitive to Imatinib Mesylate.
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| 704. |
- Casar-Borota, Olivera, et al.
(författare)
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Spindle cell oncocytoma of the adenohypophysis : report of a case with marked cellular atypia and recurrence despite adjuvant treatment.
- 2009
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Ingår i: Clinical Neuropathology. - 0722-5091. ; 28:2, s. 91-95
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Tidskriftsartikel (refereegranskat)abstract
- Spindle cell oncocytoma (SCO) of the adenohypophysis is a recently defined pituitary tumor mimicking a non-functioning macroadenoma and composed of mitochondrion rich tumor cells, positive for S-100, vimentin, epithelial membrane antigen and galectin-3 but lacking cytokeratins, pituitary hormones, and neuroendocrine markers. Derivation from pituitary folliculostellate cells (FSCs) has been suggested based upon immunohistochemical and ultrastructural characteristics shared by SCO and FSCs. 10 cases of SCO have been reported to date; of these, 8 underwent a benign clinical course and 2 recurred. We report a case of SCO with typical histologic and immunohistochemical features in addition to marked cellular pleomorphism and nuclear atypia. It showed slow regrowth over a 30-month period of follow-up despite combined surgical and radiotherapy. Despite the benign course of most reported cases, additional experience with longer follow-up are needed to assess clinical, histopathologic, and proliferative indices and their relevance to optimal therapy for this rare pituitary tumor.
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| 705. |
- Caudle, Kelly E, et al.
(författare)
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Incorporation of Pharmacogenomics into Routine Clinical Practice : the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process
- 2014
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Ingår i: Current drug metabolism. - : Bentham Science Publishers Ltd.. - 1389-2002 .- 1875-5453. ; 15:2, s. 209-217
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Tidskriftsartikel (refereegranskat)abstract
- The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
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| 706. |
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| 707. |
- Chaudhari, Aditi, et al.
(författare)
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p110alpha hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110alpha kinase activity : Kinase-independent signaling of p110 alpha mutants
- 2015
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 35:19, s. 3258-3273
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Tidskriftsartikel (refereegranskat)abstract
- The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.
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| 708. |
- Cheema, Balneek Singh, et al.
(författare)
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Association of an Osteopontin gene promoter polymorphism with susceptibility to diabetic nephropathy in Asian Indians
- 2012
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Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981. ; 413:19-20, s. 1600-1604
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Tidskriftsartikel (refereegranskat)abstract
- Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Osteopontin (OPN) has been suggested to be associated with renal diseases characterized by tubulointerstitial fibrosis and proteinuria. However, information on association of genetic polymorphisms in OPN with diabetic nephropathy is lacking. Thus, the present study was designed with the aim to examine the association of an OPN gene promoter polymorphism with diabetic nephropathy in Asian Indians. OPN C-443T (rs11730582) polymorphism was determined in 1115 type 2 diabetic patients belonging to two independently ascertained cohorts using Real time PCR based Taqman assay. We observed a nearly threefold elevated risk of diabetic nephropathy among carriers of T allele and TT genotype of OPN C-443T polymorphism. Further, this allele was found to be significantly associated with proteinuria and lower eGFR, a hallmark of diabetic nephropathy, in both our cohorts. This is the first study which suggests that OPN C-443T polymorphism may be a significant risk factor for diabetic nephropathy in type 2 diabetic patients. (C) 2012 Elsevier B.V. All rights reserved.
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| 709. |
- Chen, Yilun
(författare)
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Ultrasensitive Molecular Monitoring of Breast Cancer and Acute Myeloid Leukemia
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is the common name to a group of biologically diverse malignant neoplastic diseases. Approximately 18 million people are diagnosed with cancer annually and 8.8 million patients die from it. Tumorigenesis and progression of cancer are driven by alterations in the cancer cell genome. These alterations lead to gain of oncogenic functions, loss of tumor suppressor functions, or may be chromosomal rearrangements without obvious function, and these alterations themselves can serve as tumor-specific biomarkers that may have diagnostic and clinical utility.In this thesis, we investigated oncogenic and tumor suppressive genes in breast cancers and leukemias, with a focus on the PTEN/PIK3CA pathway as well as minimally-invasive monitoring of cancer patients using “liquid biopsies.” We studied the underlying mechanism of PTEN protein loss in breast cancer, and showed how various types of tumor-specific mutations, including those in PIK3CA, can be used as biomarkers to monitor the dynamics of occult tumor burden, evaluate the degree of tumor content dissemination into the bloodstream with mammographic compression, and detect minimal residual disease in breast cancer and acute myeloid leukemia.In Paper I, we found that the frequent loss of PTEN protein in human breast cancer is not attributable to the overexpression of the E3 ubiquitin ligase NEDD4, and thus NEDD4 is unlikely to be a regulator of the oncogenic PI3K/PTEN signaling pathway. In Paper II, we showed that serial monitoring of tumor specific chromosomal rearrangements, identified with low coverage whole genome sequencing and then measured in blood samples by digital PCR (dPCR), is a highly sensitive and specific approach to detect occult breast cancer disease prior to the onset of symptoms and clinical detection. Detected plasma ctDNA level was a quantitative predictor of poor relapse-free and overall survival. In Paper III, we confirmed the general safety of mammography, using FDA approved CellSearch® and our ultrasensitive mutation detection dPCR technology IBSAFE, that mammographic compression of the breast with a breast tumor does not appear to lead to significant additional dissemination of CTCs and ctDNA into the bloodstream. In Paper IV, we showed that acute myeloid leukemia specific mutations can be serially monitored in follow-up bone marrow samples by IBSAFE, providing an insight in subclonal evolution of the leukemia and the status of minimal residual disease.These results and our mutation detection technology suggest they have high potential to be utilized in assessing treatment response, monitoring the disease course, detecting remnant tumor deposits with targetable mutations, and helping to speed the development of new drugs in in the future.
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| 710. |
- Chinh, Bkrong, et al.
(författare)
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Whole blood gene expression in adolescent chronic fatigue syndrome : an exploratory cross-sectional study suggesting altered B cell differentiation and survival
- 2017
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group.MethodsCFS patients (12-18 years old) were recruited nation-wide to a single referral center as part of the Nor-CAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/ relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings.ResultsA total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated.ConclusionAdolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.
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