| 101. |
- De Luca, L., et al.
(författare)
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Early pharmacological treatment of acute heart failure syndromes: A systematic review of clinical trials
- 2007
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Ingår i: Acute cardiac care. - 1748-2941. ; 9:1, s. 10-21
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Tidskriftsartikel (refereegranskat)abstract
- Context: Acute Heart Failure Syndromes (AHFS) is a common admission diagnosis associated with high mortality and hospital readmissions. Given the mixed results of recent clinical trials, the early management of AHFS remains controversial. Objective: To review the recent evidence regarding current and investigational therapies for the early management of AHFS. Data Sources: A systematic search of peer-reviewed publications was performed on MEDLINE and EMBASE from January 1990 to August 2006. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts. Study Selection and Data Extraction: Criteria used for study selection were controlled study design, relevance to clinicians and validity based on venue of publication and power analysis. Data Synthesis: Although all current intravenous therapies for the early management of AHFS appear to improve hemodynamics, this may not always translate into short-term clinical benefit. Conclusion: The results of the trials conducted to date in AHFS have generally been disappointing. There is, therefore, an unmet need for new therapeutic approaches for the early management of AHFS that may improve the short-term and long-term outcomes.
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| 102. |
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| 103. |
- Ellis, W. Chadwick, et al.
(författare)
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Design of More Powerful Iron-TAML Peroxidase Enzyme Mimics
- 2009
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 131:50, s. 18052-
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Tidskriftsartikel (refereegranskat)abstract
- Environmentally useful, small molecule mimics of the peroxidase enzymes must exhibit very high reactivity in water near neutral pH. Here we describe the design and structural and kinetic characterization of a second generation of iron(III)-TAML activators with unprecedented peroxidase-mimicking abilities. Iterative design has been used to remove the fluorine that led to the best performers in first-generation iron-TAMLs. The result is a superior catalyst that meets a green chemistry objective by being comprised exclusively of biochemically common elements. The rate constants for bleaching at pH 7, 9, and 11 of the model substrate, Orange 11, shows that the new Fe-III-TAML has the fastest reactivity at pH's closer to neutral of any TAML activator to date. Under appropriate conditions, the new catalyst can decolorize Orange 11 without loss of activity for at least 10 half-lives, attesting to its exceptional properties as an oxidizing enzyme mimic.
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| 104. |
- Frye, S.A., et al.
(författare)
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Topology of the outer-membrane secretin PilQ from Neisseria meningitidis
- 2006
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Ingår i: Microbiology. - : Microbiology Society. - 1350-0872 .- 1465-2080. ; 152:12, s. 3751-3764
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria meningitidis is the causative agent of epidemic meningococcal meningitis and septicaemia. Type IV pili are surface organelles that mediate a variety of functions, including adhesion, twitching motility, and competence for DNA binding and uptake in transformation. The secretin PilQ is required for type IV pilus expression at the cell surface, and forms a dodecameric cage-like macromolecular complex in the meningococcal outer membrane. PilQ-null mutants are devoid of surface pili, and prevailing evidence suggests that the PilQ complex facilitates extrusion and retraction of type IV pili across the outer membrane. Defining the orientation of the meningococcal PilQ complex in the membrane is a prerequisite for understanding the structure-function relationships of this important protein in pilus biology. In order to begin to define the topology of the PilQ complex in the outer membrane, polyhistidine insertions in N- and C-terminal regions of PilQ were constructed, and their subcellular locations examined. Notably, the insertion epitopes at residues 205 and 678 were located within the periplasm, whereas residue 656 was exposed at the outer surface of the outer membrane. Using electron microscopy with Ni-NTA gold labelling, it was demonstrated that the insertion at residue 205 within the N-terminus mapped to a site on the arm-like features of the 3D structure of the PilQ multimer. Interestingly, mutation of the same region gave rise to an increase in vancomycin permeability through the PilQ complex. The results yield novel information on the PilQ N-terminal location and function in the periplasm, and reveal a complex organization of the membrane-spanning secretin in vivo. © 2006 SGM.
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| 105. |
- Goedecke, Julia H, et al.
(författare)
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Insulin response in relation to insulin sensitivity : an appropriate beta-cell response in black South African women.
- 2009
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 32:5, s. 860-855
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The purpose of this study was to characterize differences in the acute insulin response to glucose (AIR(g)) relative to insulin sensitivity (S(I)) in black and white premenopausal normoglycemic South African women matched for body fatness. RESEARCH DESIGN AND METHODS: Cross-sectional analysis including 57 black and white South African women matched for BMI, S(I), AIR(g), and the disposition index (AIR(g) x S(I)) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography. RESULTS: S(I) was significantly lower (4.4 +/- 0.8 vs. 9.4 +/- 0.8 and 2.9 +/- 0.8 vs. 6.0 +/- 0. 8 x 10(-5) min(-1)/[pmol/l], P < 0.001) and AIR(g) was significantly higher (1,028 +/- 255 vs. 352 +/- 246 and 1,968 +/- 229 vs. 469 +/- 246 pmol/l, P < 0.001), despite similar body fatness (30.9 +/- 1.4 vs. 29.7 +/- 1.3 and 46.8 +/- 1.2 vs. 44.4 +/- 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of beta-cell function, was not different between ethnic groups (3,811 +/- 538 vs. 2,966 +/- 518 and 3,646 +/- 485 vs. 2,353 +/- 518 x 10(-5) min, P = 0.10). Similar results were obtained for the OGTT-derived measures. CONCLUSIONS: Black South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate beta-cell response for the level of insulin sensitivity.
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| 106. |
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| 107. |
- Högbom, Martin, et al.
(författare)
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Crystal Structure of Conserved Domains 1 and 2 of the Human DEAD-box Helicase DDX3X in Complex with the Mononucleotide AMP
- 2007
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 372:1, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- DExD-box helicases are involved in all aspects of cellular RNA metabolism. Conserved domains 1 and 2 contain nine signature motifs that are responsible for nucleotide binding, RNA binding and ATP hydrolysis. The human DEAD-box helicase DDX3X has been associated with several different cellular processes, such as cell-growth control, mRNA transport and translation, and is suggested to be essential for the export of unspliced/partially spliced HIV mRNAs from the nucleus to the cytoplasm. Here, the crystal structure of conserved domains 1 and 2 of DDX3X, including a DDX3-specific insertion that is not generally found in human DExD-box helicases, is presented. The N-terminal domain 1 and the C-terminal domain 2 both display RecA-like folds comprising a central β-sheet flanked by α-helices. Interestingly, the DDX3X-specific insertion forms a helical element that extends a highly positively charged sequence in a loop, thus increasing the RNA-binding surface of the protein. Surprisingly, although DDX3X was crystallized in the presence of a large excess of ADP or the slowly hydrolyzable ATP analogue ATPγS the contaminant AMP was seen in the structure. A fluorescent-based stability assay showed that the thermal stability of DDX3X was increased by the mononucleotide AMP but not by ADP or ATPγS, suggesting that DDX3X is stabilized by AMP and elucidating why AMP was found in the nucleotide-binding pocket.
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| 108. |
- Johansson, Gunnar, et al.
(författare)
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Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors.
- 2008
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 7:5, s. 1237-45
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Tidskriftsartikel (refereegranskat)abstract
- Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001.
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| 109. |
- Karlsson, Per, 1963, et al.
(författare)
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The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer.
- 2007
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 25:15, s. 2019-26
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT). PATIENTS AND METHODS: Prognostic factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT. RESULTS: No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001). CONCLUSION: Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.
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| 110. |
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