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101.
Jamie Trotman Ruth Armstrong Helen Firth Claire Trayers James Watkins Kieren Allinson Thomas S. Jacques James C. Nicholson G. A. Amos Burke Genomics England Research Consortium Sam Behjati Matthew J. Murray Catherine E. Hook Patrick Tarpey 《British journal of cancer》2022,127(1):137
Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Methods Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Results Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Conclusion Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.Subject terms: Cancer genomics, Cancer genomics 相似文献
102.
Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3. 相似文献
103.
Huang Z Dias R Jones T Liu S Styhler A Claveau D Otu F Ng K Laliberte F Zhang L Goetghebeur P Abraham WM Macdonald D Dubé D Gallant M Lacombe P Girard Y Young RN Turner MJ Nicholson DW Mancini JA 《Biochemical pharmacology》2007,73(12):1971-1981
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast. 相似文献
105.
目的:探讨经尿道前列腺电气化术结合电切术治疗前列腺增生(BPH)并提高其安全性及有效性。方法:使用德国WOLF F24连续冲洗气化电切镜对83例BPH患者进行了经尿道前列腺电气化术加电切术治疗。结果:平均手术时间69min,无尿失禁和死亡病例,术后随访3~36个月,国际前列腺症状评分平均9.4分,残余尿量平均为21.7ml。结论:先用铲状气化切割圈切除增生的大部分前列腺组织,并进行快速、有效的止血,再用电切环修切,可快速切除增生的前列腺组织,安全有效,并发症少,值得广泛推广。 相似文献
106.
Luke Nicholson Clara Vazquez-Alfageme Piyali Sen Namritha V. Patrao Tunde Peto Yit Yang Sobha Sivaprasad Philip G. Hykin 《Eye (London, England)》2022,36(5):1086
AimsTo report, using ultra-widefield angiography (UWFA) the area, distribution, and change in retinal capillary nonperfusion (RCNP) at baseline and 100 weeks in eyes with central retinal vein occlusion (CRVO) receiving anti-VEGF for macula oedema.MethodsProspective longitudinal multi-centre cohort study. Adults with CRVO treated with anti-VEGF therapy for macular oedema underwent UWFA at baseline and week-100. The area, distribution, and change in total, peripheral and posterior pole RCNP were determined.ResultsOf 153 eyes at baseline, mean area of RCNP was 34.3DA and 12 (7.8%) had ≥75DA RCNP. More than 10DA RCNP was present in the temporal periphery in 75.8% of eyes vs. 10.5% in the nasal periphery. At week-100, mean RCNP was 42.1DA with a median change from baseline of 3.3DA 95% CI [0.4, 7.3]; p < 0.01. Of 146 eyes with ≤10DA of posterior pole RCNP at baseline, 16/146 (11.0%) progressed to >10DA at week-100. These eyes had a median increase in total RCNP of 69.7DA [95% CI 27.2–85.4] vs 0DA [0.0–1.4]; p < 0.001 for those who did not, and two developed neovascular glaucoma. Larger baseline area of RCNP and history of glaucoma were risk factors for posterior pole RCNP developing.ConclusionsWith UWFA, significant baseline RCNP was identified in the majority of CRVO patients, notably in the temporal periphery, but large increases over 100 weeks were uncommon. Development of >10DA posterior pole RCNP is a marker for widespread RCNP and in such cases the risk of anterior segment neovascularisation is not abolished by concomitant anti-VEGF therapy.Subject terms: Retinal diseases, Vision disorders 相似文献
107.
108.
目的探讨彩色多普勒超声对颅外段椎动脉发育异常的诊断价值及其临床意义。方法对2012年1月至2013年3月来我院疑诊为椎动脉型颈椎病患者进行颅外段椎动脉超声检查,观测椎动脉管腔结构、血管走行、血流信号等变化。其中152例颅外段椎动脉发育异常患者同时进行磁共振血管成像(MRA)或血管造影检查。结果发现236例患者椎动脉发育异常,其中椎动脉发育不良者为114例,椎动脉走行变异者为75例,椎动脉发育不良合并椎动脉走行变异者为47例。其中152例患者同时进行磁共振血管成像(MRA)或血管造影检查,其多普勒超声与MRA或血管造影的诊断结果完全符合。结论彩色多普勒超声能准确、快捷的诊断颅外段椎动脉发育异常,且无创、检查费用较低,具有很高的临床应用价值。 相似文献
109.
110.
H. Major J. Castro-Perez J. K. Nicholson I. D. Wilson 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(8):855-869
1. The metabolic fate of 4-bromoaniline (4-BrA) was investigated in rat following intraperitoneal administration at 50?mg kg ? 1 using HPLC-TOF-MS/MS. 2. The sensitivity provided by the use of TOF-MS/MS, aided by the distinctive isotope pattern resulting from the presence of the bromine substituent in the molecule, enabled the detection of many previously uncharacterized metabolites in the samples. 3. Several groups of minor metabolites were detected in the urine that corresponded to a number of isomeric hexose and di-hexose-containing conjugates (possibly glucosides and diglucosides) of 4-BrA. 4. As well as hexose and di-hexose conjugates of 4-BrA, several further groups of metabolites that also contained either a sulphamate or sulphate group in addition to the sugar moieties were also detected. 相似文献