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The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs are described. These prodrugs were designed as potential candidates in more selective chemotherapy by targeting hypoxic tumour tissue. Aromatic nitro and azide groups were used as the bioreductive trigger. Generation of paclitaxel occurs after reduction and subsequent 1,6-elimination or 1,8-elimination. All prodrugs are stable in buffer and indeed give paclitaxel after chemical reduction of the aromatic nitro or azide functionality. In aerobic cytotoxicity assays several prodrugs exhibit diminished cytotoxicity. These compounds are interesting candidates for further biological evaluation.  相似文献   
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The first prodrugs of camptothecin and 9-aminocamptothecin that are activated by the tumour-associated protease plasmin are reported. The tripartate prodrugs consist of a tripeptide sequence recognised by plasmin, which is linked to the 20-hydroxyl group of the camptothecins via a 1,6-elimination spacer. After selective N-protection of 9-aminocamptothecin with an Aloc group, the promoiety (tripeptide-spacer conjugate) was linked to camptothecin or 9-Aloc-9-aminocamptothecin via a 20-carbonate linkage by reacting parent drugs with the p-nitrophenyl carbonate activated promoiety in the presence of DMAP. Both prodrugs showed to be stable in buffer solution and both parent drugs were released upon incubation in the presence of plasmin. Furthermore, the prodrugs showed an average 10-fold decreased cytotoxicity with respect to their parent drugs upon incubation in seven human tumour cell lines.  相似文献   
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In an attempt to suppress the propagation of citrus greening disease in Indonesia, we explored pathogens ofDiaphorina citri which vectors the disease. At two orange orchards, manyD. citri adults were found to be dead and covered with fungal mycelia. Two fungi,Paecilomyces fumosoroseus andHirsutella citriformis, were consistently isolated from the infected insects. Molecular phylogeny of their 18S rDNA sequences showed that they belong to the ascomycetous clade of the Clavicipitales/Hypocreales, which embraces many entomopathogenic fungi. When healthy adults ofD. citri were inoculated with conidia of theP. fumosoroseus, the insects died within 6 d.  相似文献   
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Elschot M  Nijsen JF  Dam AJ  de Jong HW 《PloS one》2011,6(11):e26174

Background

Scintillation camera imaging is used for treatment planning and post-treatment dosimetry in liver radioembolization (RE). In yttrium-90 (90Y) RE, scintigraphic images of technetium-99m (99mTc) are used for treatment planning, while 90Y Bremsstrahlung images are used for post-treatment dosimetry. In holmium-166 (166Ho) RE, scintigraphic images of 166Ho can be used for both treatment planning and post-treatment dosimetry. The aim of this study is to quantitatively evaluate and compare the imaging characteristics of these three isotopes, in order that imaging protocols can be optimized and RE studies with varying isotopes can be compared.

Methodology/Principal Findings

Phantom experiments were performed in line with NEMA guidelines to assess the spatial resolution, sensitivity, count rate linearity, and contrast recovery of 99mTc, 90Y and 166Ho. In addition, Monte Carlo simulations were performed to obtain detailed information about the history of detected photons. The results showed that the use of a broad energy window and the high-energy collimator gave optimal combination of sensitivity, spatial resolution, and primary photon fraction for 90Y Bremsstrahlung imaging, although differences with the medium-energy collimator were small. For 166Ho, the high-energy collimator also slightly outperformed the medium-energy collimator. In comparison with 99mTc, the image quality of both 90Y and 166Ho is degraded by a lower spatial resolution, a lower sensitivity, and larger scatter and collimator penetration fractions.

Conclusions/Significance

The quantitative evaluation of the scintillation camera characteristics presented in this study helps to optimize acquisition parameters and supports future analysis of clinical comparisons between RE studies.  相似文献   
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Here we report an approach to generate a knock-in mouse model using an ‘ends-out’ gene replacement vector to substitute the murine Parp-1 (mParp-1) coding sequence (32 kb) with its human orthologous sequence (46 kb). Unexpectedly, examination of mutant ES cell clones and mice revealed that site-specific homologous recombination was mimicked in three independently generated ES cell clones by bidirectional extension of the vector homology arms using the endogenous mParp-1-flanking sequences as templates. This was followed by adjacent integration of the targeting vector, thus leaving the endogenous mParp-1 locus functional. A related phenomenon termed ‘ectopic gene targeting’ has so far only been described for ‘ends-in’ integration-type vectors in non-ES cell gene targeting. We provide reliable techniques to detect such ectopic gene targeting which represents an unexpected caveat in mouse genetic engineering that should be considered in the design and validation strategy of future gene knock-in approaches. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.  相似文献   
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Neandertals have been characterized as possessing features indicative of cold-climate adaptation largely based on ecogeographical morphological patterning found in recent humans. Interestingly, one character that deviates from this pattern is a relatively wide nasal aperture. The ecogeographical patterning of the nasal aperture in recent humans would predict instead that Neandertals should exhibit reduced nasal breadth dimensions. To explain this apparent anomaly it has been argued that a reduction in Neandertal nasal breadth was not possible due to dentognathic constraints on their midfaces via large anterior palatal breadth dimensions, especially large intercanine distances. A complicating factor in understanding the relationship between anterior palate breadth and nasal breadth is that both measurements are also correlated with facial prognathism. It is, therefore, unknown to what degree the relationship between anterior palate breadth and nasal breadth in Neandertals is a function of the pleisiomorphic retention of a prognathic facial skeleton. We used path analysis to test for a causal relationship between intercanine breadth and nasal breadth taking into account the potential effect of facial projection and facial prognathism (i.e., basion-nasion length and basion-prosthion length) using a large sample of geographically diverse recent and fossil Homo. Additionally, we examined the ontogenetic relationship between nasal breadth and intercanine breadth using a longitudinal human growth series to determine whether these variables exhibit similar growth trajectories. The results of these analyses indicate a weaker association between intercanine breadth and nasal breadth than expected, and that more variation in nasal breadth can be explained through basion-prosthion length rather than anterior palatal breadth dimensions. Moreover, the ontogenetic development of anterior palate breadth does not correspond to the growth trajectory of the breadth of the nose. These results explain the apparent paradox of wide piriform apertures in generally cooler climate-adapted Neandertals without resorting to dentognathic constraints, and provide additional insight into both the adaptive and nonadaptive (i.e., neutral) basis for Neandertal facial evolution.  相似文献   
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