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71.
Lasse Hjort Jakobsen Martin Bøgsted Mark Clements 《Biometrical journal. Biometrische Zeitschrift》2020,62(4):989-1011
Cure models are used in time-to-event analysis when not all individuals are expected to experience the event of interest, or when the survival of the considered individuals reaches the same level as the general population. These scenarios correspond to a plateau in the survival and relative survival function, respectively. The main parameters of interest in cure models are the proportion of individuals who are cured, termed the cure proportion, and the survival function of the uncured individuals. Although numerous cure models have been proposed in the statistical literature, there is no consensus on how to formulate these. We introduce a general parametric formulation of mixture cure models and a new class of cure models, termed latent cure models, together with a general estimation framework and software, which enable fitting of a wide range of different models. Through simulations, we assess the statistical properties of the models with respect to the cure proportion and the survival of the uncured individuals. Finally, we illustrate the models using survival data on colon cancer, which typically display a plateau in the relative survival. As demonstrated in the simulations, mixture cure models which are not guaranteed to be constant after a finite time point, tend to produce accurate estimates of the cure proportion and the survival of the uncured. However, these models are very unstable in certain cases due to identifiability issues, whereas LC models generally provide stable results at the price of more biased estimates. 相似文献
72.
FRANÇOIS X. CÔTE † SERGE GALZI † MICHEL FOLLIOT YANNICK LAMAGNÈRE PIERRE-YVES TEYCHENEY MARIE-LINE ISKRA-CARUANA 《Molecular Plant Pathology》2010,11(1):137-144
The genome of Musa balbisiana spp. contains several infectious endogenous sequences of Banana streak virus (eBSV). We have shown previously that in vitro micropropagation triggers the activation of infectious eBSOLV (endogenous sequences of Banana streak Obino l'Ewai virus ) in the synthetic tetraploid interspecific hybrid FHIA21 (AAAB). In this work, we show that another synthetic tetraploid (AAAB) hybrid and two natural triploid (AAB) plantains are equally prone to the activation of infectious eBSOLV during tissue culture. These results are a strong indication that such activation is a general phenomenon in interspecific Musa cultivars, whether synthetic or natural. We also report the first in-depth study of the correlation between the duration of tissue culture and the level of activation of infectious eBSOLV, and show that specific and common activation patterns exist in these banana plants. We hypothesize that these patterns result from the concomitant activation of infectious eBSOLV and a decrease in the virus titre in neoformed plantlets, resulting from cell multiplication outcompeting virus replication. We provide experimental data supporting this hypothesis. No activation of infectious eBSGFV (endogenous sequences of Banana streak Goldfinger virus) by tissue culture was observed in the two natural AAB plantain cultivars studied here, whereas such activation occurred in the AAAB synthetic hybrid studied. We demonstrate that this differential activation does not result from differences in the structure of eBSGFV, as all banana genomes harbour eaBSGFV-7. 相似文献
73.
The maternal determinant VegT is required for both endoderm and mesoderm formation by the Xenopus embryo. An important downstream mediator of VegT action is Xsox17, which has been proposed to be induced in cell-autonomous, then signal-dependent phases. We show that Xsox17 is a direct VegT target, but that direct induction of Xsox17 by VegT is rapidly inhibited. This inhibition is relieved by TGF- beta signalling, to which the future endoderm cell is sensitised by VegT, resulting in the observed dependence on cell contact for maintained Xsox17 expression. We propose that this change in regulation is a consequence of a VegT-induced repressor, inhibiting direct induction of early endoderm markers by VegT, and contributing to the formation of the boundary of the endodermal domain. 相似文献
74.
John S. Debenham Thomas H. Graham Andreas Verras Yong Zhang Matthew J. Clements Jeffrey T. Kuethe Christina Madsen-Duggan Wensheng Liu Urmi R. Bhatt Dunlu Chen Qing Chen Margarita Garcia-Calvo Wayne M. Geissler Huaibing He Xiaohua Li JeanMarie Lisnock Zhu Shen Xinchun Tong Dong-Ming Shen 《Bioorganic & medicinal chemistry letters》2013,23(23):6228-6233
The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose. 相似文献
75.
76.
Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway 总被引:9,自引:0,他引:9
Koffa MD Clements JB Izaurralde E Wadd S Wilson SA Mattaj IW Kuersten S 《The EMBO journal》2001,20(20):5769-5778
The role of herpes simplex virus ICP27 protein in mRNA export is investigated by microinjection into Xenopus laevis oocytes. ICP27 dramatically stimulates the export of intronless viral mRNAs, but has no effect on the export of cellular mRNAs, U snRNAs or tRNA. Use of inhibitors shows, in contrast to previous suggestions, that ICP27 neither shuttles nor exports viral mRNA via the CRM1 pathway. Instead, ICP27-mediated viral RNA export requires REF and TAP/NXF1, factors involved in cellular mRNA export. ICP27 binds directly to REF and complexes containing ICP27, REF and TAP are found in vitro and in virally infected cells. A mutant ICP27 that does not interact with REF is inactive in viral mRNA export. We propose that ICP27 associates with viral mRNAs and recruits TAP/NXF1 via its interaction with REF proteins, allowing the otherwise inefficiently exported viral mRNAs to access the TAP-mediated export pathway. This represents a novel mechanism for export of viral mRNAs. 相似文献
77.
Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis 下载免费PDF全文
Arita K South AP Hans-Filho G Sakuma TH Lai-Cheong J Clements S Odashiro M Odashiro DN Hans-Neto G Hans NR Holder MV Bhogal BS Hartshorne ST Akiyama M Shimizu H McGrath JA 《American journal of human genetics》2008,82(1):73-80
Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1–q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor β (OSMRβ), in three families. OSMRβ is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching. 相似文献
78.
The present study investigated whether the serotonergic system is involved in mediating the behavioral effects of corticotropin-releasing hormone (CRH) in juvenile spring chinook salmon, Oncorhynchus tshawytscha. An intracerebroventricular (ICV) injection of CRH induced hyperactivity. The effect of CRH was potentiated in a dose-dependent manner by the concurrent administration of the serotonin (5-HT) selective reuptake inhibitor fluoxetine. However, administration of fluoxetine alone had no effect on locomotor activity, suggesting that the locomotor-stimulating effect of CRH is mediated by the activation of the serotonergic system. Conversely, ICV injections of the 5-HT(1A) receptor antagonist NAN-190 attenuated the effect of CRH on locomotor activity when given in combination with CRH but had no effect when administered alone. These results provide the first evidence to support the hypothesis that the effect of CRH on locomotor activity in teleosts is mediated by activating the serotonergic system. 相似文献
79.
Kjer-Nielsen L Clements CS Brooks AG Purcell AW McCluskey J Rossjohn J 《Structure (London, England : 1993)》2002,10(11):1521-1532
Despite a potential repertoire of >10(15) alphabeta T cell receptors (TcR), the HLA B8-restricted cytolytic T cell response to a latent antigen of Epstein-Barr virus (EBV) is strikingly limited in the TcR sequences that are selected. Even in unrelated individuals this response is dominated by a single highly restricted TcR clonotype that selects identical combinations of hypervariable Valpha, Vbeta, D, J, and N region genes. We have determined the 1.5 A crystal structure of this "public" TcR, revealing that five of the six hypervariable loops adopt novel conformations providing a unique combining site that contains a deep pocket predicted to overlay the HLA B8-peptide complex. The findings suggest a structural basis for the immunodominance of this clonotype in the immune response to EBV. 相似文献
80.
Structure and autoregulation of the yeast Hst2 homolog of Sir2 总被引:6,自引:0,他引:6