| 1. |
- Davies, James S, et al.
(författare)
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Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus
- 2019
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:1, s. 52-66
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Tidskriftsartikel (refereegranskat)abstract
- N‐Acetylglucosamine‐6‐phosphate deacetylase (NagA) and glucosamine‐6‐phosphate deaminase (NagB) are branch point enzymes that direct amino sugars into different pathways. For Staphylococcus aureus NagA, analytical ultracentrifugation and small‐angle X‐ray scattering data demonstrate that it is an asymmetric dimer in solution. Initial rate experiments show hysteresis, which may be related to pathway regulation, and kinetic parameters similar to other bacterial isozymes. The enzyme binds two Zn2+ ions and is not substrate inhibited, unlike the Escherichia coli isozyme. S. aureus NagB adopts a novel dimeric structure in solution and shows kinetic parameters comparable to other Gram‐positive isozymes. In summary, these functional data and solution structures are of use for understanding amino sugar metabolism in S. aureus, and will inform the design of inhibitory molecules.
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| 2. |
- Edwards, David, et al.
(författare)
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99mTc-NC100668, an agent for imaging venous thromboembolism : The effect of anticoagulant or thrombolytic therapy on the uptake and retention of radioactivity in blood clots in vivo
- 2007
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Ingår i: Nuclear medicine communications. - : Ovid Technologies (Wolters Kluwer Health). - 0143-3636 .- 1473-5628. ; 28:1, s. 55-62
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The purpose of this study was to evaluate the uptake of Tc-NC100668 into blood clots and elucidate the potential for medications commonly used to treat thromboembolism to interfere with the uptake and retention of Tc-NC100668. METHODS: Tc-NC100668 in vivo uptake and retention in a range of blood clot of various ages (up to 4 h old) and in the presence of anticoagulants or thrombolytic therapies was measured in a rat model of deep vein thrombosis. RESULTS: Tc-NC100668 was rapidly absorbed into and retained by blood clots and was not significantly affected by the presence of unfractionated or low molecular weight heparin or thrombin inhibitor. Tissue plasminogen activator reduced the uptake of Tc-NC100668 into blood clot by a factor of 3 when adjusted to allow for changes in the weight of the blood clot. CONCLUSIONS: This study has demonstrated that the uptake and retention of Tc-NC100668 into blood clots in the rat model of deep vein thrombosis is rapid and maintained over at least a 4 h post-injection period. It has been shown that Tc-NC100668 is retained in blood clots even in the presence of therapeutic doses of those anticoagulant and thrombolytic therapies typically used to treat pulmonary embolism and venous thrombosis.
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| 3. |
- Edwards, David, et al.
(författare)
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Tc-99m-NC100668, a new tracer for imaging venous thromboemboli : pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro
- 2006
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 33:11, s. 1258-1265
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Tc-99m-NC100668 is a new radiotracer being developed to aid the diagnosis of thromboembolism. The structure of NC100668 is similar to a region of human alpha(2)-antiplasmin, which is a substrate for factor XIIIa (FXIIIa). The purpose of this study was to confirm the uptake of Tc-99m-NC100668 into forming plasma clot and to establish the biodistribution of Tc-99m-NC100668 in Wistar rats. Methods: The in vitro plasma clot uptake of Tc-99m-NC100668 and other compounds with known affinities to FXIIIa was measured using a plasma clot assay. The biodistribution and blood clot uptake of radioactivity of Tc-99m-NC100668 in normal Wistar rats and those bearing experimentally induced deep vein thrombi were investigated. Results: The in vitro uptake of Tc-99m-NC100668 was greater than that for [C-14] dansyl cadaverine, a known substrate of FXIIIa in the plasma clot assay. The biodistribution of Tc-99m-NC100668 in male and female Wistar rats up to 24 h p.i. showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention. In vivo the uptake and retention of Tc-99m-NC100668 into the blood clot was greater than could be accounted for by non-specific accumulation of the radiotracer within the blood clot. Conclusion: Tc-99m-NC100668 was retained by plasma clots in vitro and blood clots in vivo. No significant tissue retention which could interfere with the ability to image thrombi in vivo was observed. This evidence suggests that Tc-99m-NC100668 might be useful in the detection of thromboembolism.
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| 4. |
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| 5. |
- Edwards, David, et al.
(författare)
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The in vivo and in vitro metabolic profile of 99mTc-NC100668, a new tracer for imaging venous thromboembolism : identification and biodistribution of the principal radiolabeled metabolite
- 2006
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 34:7, s. 1128-1135
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Tidskriftsartikel (refereegranskat)abstract
- (99m)Tc-NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is a radiopharmaceutical imaging agent being developed to aid the diagnosis of thromboembolism. The stability profile of (99m)Tc-NC100668 was investigated by high-performance liquid chromatography (HPLC) after in vitro exposure to blood and plasma obtained from rat and human, as well as to urine and bile obtained from rat. The metabolic profile of (99m)Tc-NC100668 exposed to human and rat hepatic S9 (a liver homogenate-rich cytochrome P450) was also studied. The profile of (99m)Tc-labeled species in plasma, urine, and bile was investigated following i.v. administration of (99m)Tc-NC100668 to rat. The major species observed in vitro and in vivo consisted of the (99m)Tc-chelator (NC100194) [N,N-Bis(N-(1,1-dimethyl-2-(hydroxylimino-)propyl)aminoethyl)aminoethylamine] attached to the C-terminal amino acid residue and referred to as (99m)Tc-complex of Gly-NC100194. The identity of the major metabolite was confirmed by cochromatography with an authentic standard and the genuine metabolite using a second HPLC method. The minor metabolites were sodium pertechnetate ((99m)Tc) and (99m)Tc-NC100194. In addition, a small number of other species were transiently observed in vitro; they were not investigated further. The biodistribution of the major metabolite was studied in male Wistar rats. The affinity of the major metabolite toward plasma clot was established using a plasma clot-forming assay. A minor uptake of (99m)Tc-complex of Gly-NC100194 in the plasma clot and a rapid removal from the body were noted. In conclusion, the metabolites of (99m)Tc-NC100668 are not anticipated to have a negative impact on the ability of the test substance to image blood clots.
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| 6. |
- Inabnet, William B., 3rd, et al.
(författare)
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Correlating the Bethesda System for Reporting Thyroid Cytopathology with Histology and Extent of Surgery : A Review of 21,746 Patients from Four Endocrine Surgery Registries Across Two Continents
- 2020
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Ingår i: World Journal of Surgery. - : Springer. - 0364-2313 .- 1432-2323. ; 44:2, s. 426-435
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Bethesda system for cytopathology (TBSRTC) is a 6-tier diagnostic framework developed to standardize thyroid cytopathology reporting. The aim of this study was to determine the risk of malignancy (ROM) for each Bethesda category.METHODS: Thyroidectomy-related data from 314 facilities in 22 countries were entered into the following outcome registries: CESQIP (North America), Eurocrine (Europe), SQRTPA (Sweden) and UKRETS (UK). Demographic, cytological, pathologic and extent of surgery data were mapped into one dataset and analyzed.RESULTS: Out of 41,294 thyroidectomy patient entries from January 1, 2015, to June 30, 2017, 21,746 patients underwent both thyroid FNA and surgery. A comparison of cytology and surgical pathology data demonstrated a ROM for Bethesda categories 1 to 6 of 19.2%, 12.7%, 31.9%, 31.4%, 77.8% and 96.0%, respectively. Male patients had a higher rate of malignancy for every Bethesda category. Secondary analysis demonstrated a high ROM in male patients with Bethesda 3 category aged 31-35 years (52.1%, 95% confidence interval (CI) 37.9-66.2%), aged 36-40 years (55.9%, 95% CI 39.2-72.6%) and aged 41-45 years (46.9%, 95% CI 33-60.9%). Patients with Bethesda 5 and 6 scores were more likely to undergo total thyroidectomy (65.9% and 84.6%); for patients with Bethesda scores 2 and 3, a higher percentage of females underwent total thyroidectomy compared to males in spite of a higher ROM for males.CONCLUSIONS: These data demonstrate that Bethesda categories 1-4 are associated with a higher ROM compared to the first edition of TBSRTC, especially in male patients, and validate findings from the second edition of TBSRTC.
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| 7. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 8. |
- Niederle, Bruno, et al.
(författare)
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Multiple Endocrine Neoplasia Type 1 and the Pancreas : Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement
- 2021
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 111:7, s. 609-630
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Forskningsöversikt (refereegranskat)abstract
- The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
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| 9. |
- Preece, Paul, et al.
(författare)
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Amyloid precursor protein mRNA levels in Alzheimer's disease brain
- 2004
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Ingår i: Brain Research. Molecular Brain Research. - : Elsevier BV. - 0169-328X .- 1872-6941. ; 122:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.
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| 10. |
- Preece, Paul, et al.
(författare)
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An optimistic view for quantifying mRNA in post-mortem human brain
- 2003
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Ingår i: Brain Research. Molecular Brain Research. - 0169-328X .- 1872-6941. ; 116:1-2, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative human mRNA data are derived from post-mortem or biopsied tissue. RNA degradation, poor replication, a large mRNA variance and confounding factors such as brain pH and age of death are often cited, however, as objections to the data's reliability. A central question is whether post-mortem human mRNA can be treated as a statistically ordered system. TaqMan real-time RT-PCR was used to measure seven mRNAs in 513 cortical samples taken from 90 Alzheimer's disease and 81 control brains. Despite a high mRNA variance strong correlations were found between the mRNA transcripts in a single brain. Where a brain has a high/low level of one mRNA, the same brain invariably has a high/low level of other mRNAs; correlated order is present and allows removal of that source of variation common to all genes. Although levels of mRNA are highly variable between subjects (>1000-fold), quantitative order is present in post-mortem human mRNA, allowing effects due to pathology or gender to be isolated and tested for significance.
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