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- Killela, Patrick J., et al.
(författare)
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TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:15, s. 6021-6026
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (>= 15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
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- Voight, Benjamin F, et al.
(författare)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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- Kooner, Jaspal S, et al.
(författare)
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Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
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- Stegmayr, Bernd, et al.
(författare)
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Beyond dialysis : Current and emerging blood purification techniques
- 2012
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Ingår i: Seminars in dialysis. - 0894-0959 .- 1525-139X. ; 25:2, s. 207-213
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Tidskriftsartikel (refereegranskat)abstract
- Extracorporeal blood purification using various techniques and hardware is a major part of the modern day practice of clinical nephrology. Although the various modalities of hemodialysis and hemofiltration are the most commonly used extracorporeal therapies in clinical nephrology, blood purification using other techniques have become necessary to remove pathogenic, toxic, or waste substances not easily cleared by hemodialysis or hemofiltration due to factors such as molecular size, protein binding, and lipid solubility. The following review is an up to date summary of extracorporeal therapies, beyond hemodialysis and hemofiltration, in current clinical use as practiced by nephrologists and others in the United States and beyond. This comprises therapeutic apheresis (plasma exchange and cytapheresis), plasma adsorption, hemoperfusion, and the bio-artificial devices.
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- Stegmayr, Bernd, et al.
(författare)
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Septic shock with multiorgan failure : From conventional apheresis to adsorption therapies
- 2012
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Ingår i: Seminars in dialysis. - 0894-0959 .- 1525-139X. ; 25:2, s. 171-175
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Tidskriftsartikel (refereegranskat)abstract
- Septic shock is often associated with multiorgan failure, a life threatening clinical condition during which there is an imbalance in the proinflammatory and anti-inflammatory cytokines, chemokines, antigens, endotoxins, procoagulant, and anticoagulant factors and also resultant effects of therapeutic intervention like volume overload. Various extracorporeal therapies have shown some positive results as adjunctive therapeutic intervention to traditional antimicrobials in an effort to bring the inflammatory mediators to a homeostatic balance and to improve poor organ perfusion caused by hypotension and thrombosis in the microcirculation. This review focuses on current information on the use of therapeutic apheresis procedures as adjunctive therapy in such clinical situations as well as the exciting prospects for the near future. The sometimes disappointing results of early phase clinical studies may, in some cases, be related to the well known barriers to successful clinical trials in critically ill patients rather than to failure of the novel concept of adjunctive extracorporeal treatment of septic shock. It should be noted that some of the specialized apheresis technologies reviewed in this article are not yet available for clinical use in the United States as they are not yet approved for use by the US Food and Drug Administration.
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