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160 results on '"Gentle, D."'

1. Laser-cooled ytterbium ion frequency standard

Author

Mulholland, S., Klein, H. A., Barwood, G. P., Donnellan, S., Gentle, D., Huang, G., Walsh, G., Baird, P. E. G., and Gill, P.

Subjects
Physics - Atomic Physics
Abstract

We report on the development of a trapped-ion, microwave frequency standard based on the 12.6 GHz hyperfine transition in laser-cooled ytterbium-171 ions. The entire system fits into a 6U 19-inch rack unit ($51\times49\times28$ cm) and comprises laser, electronics, and physics package subsystems. The performance of this development system is evaluated; the fractional frequency instability was measured to be $3.6\times10^{-12}/\surd\tau$ for averaging times between 30 s and 1500 s., Comment: 16 Pages, 10 figures; v3 as published in Applied Physics B

Published
2018
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11. CCEM key comparison CCEM.RF-K23.F

Author

Guerrieri, J, primary, Coder, J, additional, MacReynolds, K, additional, Tamura, D, additional, Gentle, D G, additional, Beardmore, A, additional, Eio, C, additional, Budovsky, I, additional, Ji, Y, additional, Warner, F M, additional, Wei-long, W, additional, Donglin, M, additional, Dražil, K, additional, Sage, Y Le, additional, Allal, D, additional, Hirose, M, additional, Kurokawa, S, additional, Komiyama, K, additional, Sergey, K, additional, Sergey, N, additional, Kang, J-S, additional, Kang, N-W, additional, Fast, L, additional, Karlsson, K, additional, Carlsson, Jan, additional, Pythoud, F, additional, ÇAKIR, S, additional, and Cetintas, M, additional

Published
2016
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12. Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma

Author

Jafri, M, Wake, NC, Ascher, DB, Pires, DEV, Gentle, D, Morris, MR, Rattenberry, E, Simpson, MA, Trembath, RC, Weber, A, Woodward, ER, Donaldson, A, Blundell, TL, Latif, F, Maher, ER, Jafri, M, Wake, NC, Ascher, DB, Pires, DEV, Gentle, D, Morris, MR, Rattenberry, E, Simpson, MA, Trembath, RC, Weber, A, Woodward, ER, Donaldson, A, Blundell, TL, Latif, F, and Maher, ER

Abstract

UNLABELLED: Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC. SIGNIFICANCE: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.

Published
2015

23. Germline mutations in dis3l2 cause the perlman syndrome of overgrowth and wilms tumor susceptibility

Author

Astuti, D., Morris, M.R., Cooper, W.N., Staals, R.H.J., Wake, N.C., Fews, G.A., Gill, H., Gentle, D., Shuib, S., Ricketts, C.J., Cole, T., Essen, A.J. van, Lingen, R.A. van, Neri, G., Opitz, J.M., Rump, P., Stolte-Dijkstra, I., Muller, F., Pruijn, G.J.M., Latif, F., Maher, E.R., Astuti, D., Morris, M.R., Cooper, W.N., Staals, R.H.J., Wake, N.C., Fews, G.A., Gill, H., Gentle, D., Shuib, S., Ricketts, C.J., Cole, T., Essen, A.J. van, Lingen, R.A. van, Neri, G., Opitz, J.M., Rump, P., Stolte-Dijkstra, I., Muller, F., Pruijn, G.J.M., Latif, F., and Maher, E.R.

Abstract

Item does not contain fulltext

Published
2012

24. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.

Author

Astuti, D, Morris, Mr, Cooper, Wn, Staals, Rh, Wake, Nc, Fews, Ga, Gill, H, Gentle, D, Shuib, S, Ricketts, Cj, Cole, T, Van Essen, Aj, Van Lingen, Ra, Neri, Giovanni, Opitz, Jm, Rump, P, Stolte Dijkstra, I, Müller, F, Pruijn, Gj, Latif, F, Maher, Er, Astuti, D, Morris, Mr, Cooper, Wn, Staals, Rh, Wake, Nc, Fews, Ga, Gill, H, Gentle, D, Shuib, S, Ricketts, Cj, Cole, T, Van Essen, Aj, Van Lingen, Ra, Neri, Giovanni, Opitz, Jm, Rump, P, Stolte Dijkstra, I, Müller, F, Pruijn, Gj, Latif, F, and Maher, Er

Abstract

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.

Published
2012

27. INFLUENCE OF CT AUTOMATIC TUBE CURRENT MODULATION ON UNCERTAINTY IN EFFECTIVE DOSE.

Author

Sookpeng, S., Martin, C. J., and Gentle, D. J.

Subjects
RADIATION dosimetry, COMPUTED tomography, TOMOGRAPHY image quality, IMAGING phantoms, TREATMENT effectiveness
Abstract

Computed tomography (CT) scanners are equipped with automatic tube current modulation (ATCM) systems that adjust the current to compensate for variations in patient attenuation. CT dosimetry variables are not defined for ATCM situations and, thus, only the averaged values are displayed and analysed. The patient effective dose (E), which is derived from a weighted sum of organ equivalent doses, will be modified by the ATCM. Values for E for chest-abdomen-pelvis CT scans have been calculated using the ImPACT spreadsheet for patients on five CT scanners. Values for E resulting from the z-axis modulation under ATCM have been compared with results assessed using the same effective mAs values with constant tube currents. Mean values for E under ATCM were within ±10 % of those for fixed tube currents for all scanners. Cumulative dose distributions under ATCM have been simulated for two patient scans using single-slice dose profiles measured in elliptical and cylindrical phantoms on one scanner. Contributions to the effective dose from organs in the upper thorax under ATCM are 30-35 % lower for superficial tissues (e.g. breast) and 15-20 % lower for deeper organs (e.g. lungs). The effect on doses to organs in the abdomen depends on body shape, and they can be 10-22 % higher for larger patients. Results indicate that scan dosimetry parameters, dose-length product and effective mAs averaged over the whole scan can provide an assessment in terms of E that is sufficiently accurate to quantify relative risk for routine patient exposures under ATCM. [ABSTRACT FROM AUTHOR]

Published
2016
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30. Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

Author

Astuti, D., primary, Ricketts, C. J., additional, Chowdhury, R., additional, McDonough, M. A., additional, Gentle, D., additional, Kirby, G., additional, Schlisio, S., additional, Kenchappa, R. S., additional, Carter, B. D., additional, Kaelin, W. G., additional, Ratcliffe, P. J., additional, Schofield, C. J., additional, Latif, F., additional, and Maher, E. R., additional

Published
2010
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43. A study of CT dose distribution in an elliptical phantom and the influence of automatic tube current modulation in the x-y plane.

Author

Sookpeng, S., Martin, C. J., and Gentle, D. J.,

Subjects
COMPUTED tomography, IMAGING phantoms, ABSORBED dose, BODY composition models, MEDICAL technology
Abstract

Computed tomography (CT) performance assessments relating to patient dose to the body are made conventionally in 320 mm diameter cylindrical acrylic phantoms. The cross section of the human trunk is closer to an ellipse and automatic tube current modulation (ATCM) systems adjust the exposure level with orientation in the x-y plane, changing the dose distribution within the body. This study has investigated differences in the distributions of dose within a standard cylindrical body phantom and an elliptical dosimetry phantom for Toshiba, General Electric and Philips CT scanners, and recorded changes with the application of the ATCM. Single slice dose profiles have been recorded within the phantoms using Gafchromic film. CT dose indices along 100 mm lengths have been calculated and data sets combined to simulate helical scans, from which values for cumulative doses have been derived. The doses in the centre of the elliptical phantom are 70-100% larger than for the cylindrical one and in the anterior are around 20-40% larger, while the doses in the lateral positions are similar for the two phantom shapes. The differences between the anterior and lateral doses were larger for the Toshiba scanner and this is thought to be linked to the narrower profile of the beam produced by the bow-tie filter. When the ATCM mode for the Toshiba scanner is implemented, the doses in the anterior and posterior positions are reduced preferentially, bringing them closer to the doses in the lateral positions. [ABSTRACT FROM AUTHOR]

Published
2013
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44. Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas

Author

Margetts, C D E, Astuti, D, Gentle, D C, Cooper, W N, Cascon, A, Catchpoole, D, Robledo, M, Neumann, H P H, Latif, F, and Maher, E R

Abstract

Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHBand SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novopromoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1(82%) and CASP8(31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (P<0.001). This suggests that 11p15.5-imprinted genes may be implicated in the pathogenesis of both familial (germline VHLand SDHDmutations) and sporadic phaeochromocytomas.

Published
2005
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45. Potential role for monocyte chemotactic protein-4 (MCP-4) in monocyte/macrophage recruitment in acute renal inflammation

Author

Chakravorty, S.J., Howie, A.J., Girdlestone, J., Gentle, D., and Savage, C.O.S.

Abstract

The CC chemokine, monocyte chemoattractant protein-4 (MCP-4), is an important chemoattractant for monocytes and T cells. Recent data indicate a role in renal inflammation. This study has used in situ hybridization and immunohistochemical analysis of cryostat sections of biopsy material taken from patients with acute renal allograft rejection and vasculitic glomerulonephritis to demonstrate renal expression of MCP-4, both at message and protein level. MCP-4 was primarily expressed at peritubular, periglomerular, and perivascular sites, irrespective of the inflammatory condition, and was associated with infiltrating CD3-positive lymphocytes and CD68-positive monocyte/macrophages. In addition, proximal tubular epithelial cells grown in culture from cortical fragments of human kidney showed low levels of constitutive MCP-4 expression, detectable by western blotting; this expression of MCP-4 was up-regulated in response to the pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). CCR3-, CCR5- and CCR2-expressing leukocyte populations were identified at sites of MCP-4 expression. Double-staining techniques revealed that CC chemokine receptor-expressing cells were primarily CD68-positive. These studies suggest an important role for MCP-4 in the recruitment and retention of monocytes/macrophages in renal inflammation. Copyright © 2001 John Wiley & Sons, Ltd.

Published
2001

49. Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.

Author

Bailly, C, Donkor, I O, Gentle, D, Thornalley, M, and Waring, M J

Abstract

Footprinting experiments using both DNase I and methidium propyl-EDTA.Fe(II) have been used to investigate the sequence selectivity in binding to DNA of pentamidine and four butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with acquired immunodeficiency syndrome. In common with pentamidine, the butamidine drugs, which contain cis- or trans-1,4-but-2-ene linkers and either bis(amidine) or bis(imidazolidine) terminal groups, bind selectively to DNA sequences composed of at least 4 consecutive A.T base pairs. None of the drugs tolerates the presence of a G.C base pair within the binding site. Consistently in the DNase I and methidium propyl-EDTA.Fe(II) footprinting experiments, the cis-isomers produce stronger footprints than do the trans-isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that the conformation of the drug plays a determining role in the binding reaction. Starting from the known structure of a pentamidine-oligonucleotide complex, it is possible to rationalize the different capacities of the cis- and trans-butamidine analogues to recognize defined DNA sequences in terms of the radius of curvature of the molecule and the distance between the positively charged terminal groups. Together, these features constitute critical factors favoring (cis-conformation) or hampering (trans-conformation) the fitting of the drugs into the minor groove of DNA. In terms of structure-activity relationships, the AT-specific recognition of DNA by this series of butamidine derivatives cannot be directly correlated with their potencies against Pneumocystis carinii pneumonia.

Published
1994

50. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma

Author

Morris, M. R., Hughes, D. J., Tian, Y. -M, Ricketts, C. J., Lau, K. W., Gentle, D., Shuib, S., Serrano-Fernandez, P., Jan Lubinski, Wiesener, M. S., Pugh, C. W., Latif, F., Ratcliffe, P. J., and Maher, E. R.

Subjects
urologic and male genital diseases, neoplasms, female genital diseases and pregnancy complications
Abstract

BACKGROUND: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-1alpha and -2alpha is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-1alpha and HIF-2alpha share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-1alpha expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-1alpha and HIF-2alpha contribute to renal tumourigenesis was investigated here. MATERIALS AND METHODS: Mutation analysis of the complete coding sequence of HIF-1alpha and HIF-2alpha was carried out in primary RCC (n=40). RESULTS: The analysis revealed a somatic HIF1A missense substitution, p.Val116Glu, in a single RCC. Functional studies demonstrated that p.Val116Glu impaired HIF-1alpha transcriptional activity. Genotyping of HIF1A variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls. CONCLUSION: The detection of a loss-of-function HIF1A mutation in a primary RCC is consistent with HIF-1 and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIF1A are not frequently implicated in the pathogenesis of RCC.

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