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| 2. |
- Imai, Y., et al.
(författare)
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Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury
- 2008
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 133:2, s. 235-249
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Tidskriftsartikel (refereegranskat)abstract
- Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.
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| 4. |
- Iacopetta, B, et al.
(författare)
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Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.
- 2006
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. - : Elsevier BV. - 0923-7534. ; 17:5, s. 842-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.
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| 5. |
- Gibney, James, et al.
(författare)
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Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women.
- 2005
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 90:7, s. 3897-903
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The endocrine and metabolic functions of the liver are affected by estrogen. Oral estrogen reduces IGF-I and suppresses fat oxidation despite augmenting GH secretion. The aim of this study was to determine whether selective estrogen receptor modulators display similar effects and whether these effects are magnified in GH-deficient (GHD) women because of the loss of GH feedback. DESIGN: This was an open-label, randomized, two-period, crossover study comparing treatment (raloxifene vs. estradiol) and group (normal vs. GHD). SETTING: The setting of this study was a clinical research unit. PARTICIPANTS: Twelve postmenopausal women and 12 women with hypopituitarism participated in this study. INTERVENTION: Two 4-wk treatments with 17beta-estradiol (E2; 2 mg, followed by 4 mg) or raloxifene (60 mg, followed by 120 mg) were given, crossing over to the alternate treatment after a 4-wk washout period. OUTCOME MEASURES: Endocrine [GH, IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein, and SHBG] and metabolic (fat oxidation) end points were used as outcome measures. RESULTS: E2 reduced serum IGF-I levels in a dose-dependent manner in both groups, with effects greater (P < 0.05) than raloxifene. Raloxifene reduced IGF-I levels in the GHD group (P < 0.001), but not in the postmenopausal group. E2 reduced (P < 0.05), and raloxifene increased (P < 0.05), IGFBP-3 levels in both groups. E2, but not raloxifene, increased GH (P < 0.05) in postmenopausal women. The effects of E2 and raloxifene on IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, GH-binding protein, and SHBG were significantly different (P < 0.05). E2 and raloxifene reduced (P < 0.05) fat oxidation equally in GHD, whereas the decrease in postmenopausal women was not significant. CONCLUSION: E2 and raloxifene exert different hepatic endocrine, but not lipid oxidative, effects. The greater effects seen in GHD women may be explained by the loss of endogenous GH feedback.
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| 7. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Independent and combined effects of testosterone and growth hormone on extracellular water in hypopituitary men.
- 2005
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 90:7, s. 3989-94
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Symptoms of fluid retention in GH-deficient patients during GH replacement are greater in men than in women, suggesting that testosterone may augment or estradiol may attenuate the antinatriuretic actions of GH. The mechanisms underlying the sodium-retaining effects of GH are poorly understood. AIM: The aim of this study was to investigate the effects of GH and testosterone, alone and in combination, on extracellular water (ECW) and the hormonal mechanisms involved. DESIGN: Two separate, open-label, randomized, two-period, crossover studies were performed; the first compared the effects of GH alone with those of GH and testosterone, and the second compared the effects of testosterone alone with those of GH and testosterone. PARTICIPANTS: Twelve hypopituitary men with GH deficiency and hypogonadism were studied. INTERVENTION: During the weeks of intervention, GH (0.5 mg/d) and testosterone enanthate (250 mg) were administered by im injection. OUTCOME MEASURES: The outcome measures were ECW, IGF-I, plasma renin activity (PRA), aldosterone (Aldo), and atrial natriuretic peptide (ANP). RESULTS: GH treatment significantly increased (P < 0.05) both IGF-I and ECW, and these changes were enhanced by cotreatment with testosterone (P = 0.07 for both). PRA, Aldo, and ANP levels did not change. Testosterone treatment alone did not change the IGF-I concentration, whereas cotreatment with GH induced a marked increase. Testosterone alone increased (P < 0.05) ECW, and the effect was augmented (P < 0.01) by cotreatment with GH. Although PRA and ANP did not change, plasma Aldo decreased after single and combined treatments. CONCLUSION: GH and testosterone exerted independent and additive effects on ECW. The mechanisms of fluid retention for both hormones are likely to be exerted on the renal tubules. This is the first direct evidence that testosterone increases ECW.
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| 9. |
- Lau, Buon Kiong, et al.
(författare)
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Transformations for nonideal uniform circular arrays operating in correlated signal environments
- 2006
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Ingår i: IEEE Transactions on Signal Processing. - 1053-587X. ; 54:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- The Davies transformation is a method to transform the steering vector of a uniform circular array (UCA) to one with Vandermonde form. As such, it allows techniques such as spatial smoothing for direction-of-arrival (DOA) estimation in a correlated signal environment, developed originally for uniform linear arrays, to be applied to UCAs. However, the Davies transformation can be highly sensitive to perturbations of the underlying array model. This paper presents a method for deriving a more robust transformation using optimization techniques. The effectiveness of the method is illustrated through a number of DOA estimation examples.
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