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41.
    
The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.  相似文献   
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43.
Experiments were carried out in vivo and in vitro with four isolates of Penicillium expansum (I 1, E 11, C 28 and I 12) to evaluate their aggressiveness, growth and patulin accumulation in both usual (pears and apples) and less common hosts (apricots, peaches, strawberries and kiwifruits) of the pathogen. The 75% of isolates showed the ability to cause blue mould in all tested hosts. In particular, C 28 and I 1 were the most and the least aggressive isolates, respectively (52.9 and 10.6% infection and 20.7 and 15.4 mm lesion diameters). ‘Candonga’ strawberries and ‘Pinkcot’ apricots showed the largest lesion diameters (29.8 and 25.3 mm), followed by ‘Conference’ pears, ‘Spring Crest’ peaches and ‘Abate Fetel’ pears. With the exception of ‘Candonga’ strawberries, the formation of colonies and mycelial growth of P. expansum isolates on fruit puree agar media (PAMs) was stimulated in comparison to a standard growth medium (malt extract agar, MEA). Two of the most aggressive isolates in our assays (I 12 and C 28) showed the greatest accumulation of patulin both in vitro and in vivo, while the least aggressive isolate (I 1) produced patulin only in a few growth media and cvs. Patulin concentration on fruit PAMs was higher than patulin detected in infected fruit tissues. Apple PAMs were the more favorable substrates for patulin accumulation in vitro (maximum concentration 173.1 and 74.1 μg/mL in ‘Pink Lady and ‘Golden Delicious’ PAMs, respectively) and ‘Pink Lady’ apples inoculated with the isolate E 11 showed the greatest accumulation of patulin in the whole in vivo assay (33.9 μg/mL). However, infected tissue of cv Golden Delicious showed lower average accumulation of patulin (1.7 μg/mL) than that of cv Pink Lady (19.1 μg/mL), and no significant differences in patulin concentrations were found among ‘Golden Delicious’ apples and tested cvs of pears, kiwifruits and strawberries. Peaches were highly susceptible to patulin accumulation, showing average concentrations of 27.4 and 18.6 μg/mL in vitro and in vivo, respectively. Apricots were also consistently positive for patulin accumulation, both in vitro (average values of 20.1 μg/mL) and in vivo (average values of 9.4 μg/mL). Our study showed the potential of some less common hosts of P. expansum (in particular peaches and apricots) to support patulin production, indicating that a steady monitoring of patulin contamination should be carried out in fruit substrates other than apples and pears.  相似文献   
44.
Plant productivity and fruit quality in terms of occurrence of mineral elements and metabolites were determined on wild bilberry growing in open and forest stands in a protected area of N‐Italy. Plant productivity was significantly higher in open stands (3 ± 2.5 compared with 0.03 ± 0.05 fruits per plant) suggesting that both collections in the wild and semi‐wild cultivation should be planned in open habitats. Results obtained by ionomic and metabolomic analyses indicated that high quality fruits can be collected in the analyzed area and their nutritional profile did not differ between open and forest stands. Cyanidin and delphinidin proportion of bilberries from our study area was respectively 23.8% and 43.9% of total antocyanin and it is similar to that previously considered peculiar to bilberry fruits of high latitude regions of Europe and indicative of high quality food properties. A comparison between wild bilberry collected in the protected area and commercial blueberry was also performed and relevant differences between them detected, confirming the concept that wild bilberry has a better nutritional profile than blueberry. Practical Application Bilberry fruits provide relevant nutrients to human diet. However, the scarce availability in the wild is a limiting factor hindering a wider use of this product. In this study we compared plant productivity and nutritional profile of bilberry growing in open and forest sites, demonstrating that they do not differ in terms of mineral and metabolomic contents, whereas plant productivity is by far higher in open sites. This supports the possibility to obtain bilberry fruits by semiwild cultivation maintaining open sites that are also crucial for biodiversity conservation in mountain areas.  相似文献   
45.
The aim of this study was to evaluate the packaging and processing parameters that produce sulphide black in corned beef. Twenty experimental batches were prepared, and in order to evaluate the effect of the packaging manufacturing process, variations were introduced in the tin layer, in the cure of lacquer applied inside and in the presence or absence of superficial scratches in the lacquer. Processing parameters, such as sterilising time and temperature as well as filling temperatures, were evaluated. The visual evaluation carried out to check the occurrence of black spots and the statistical analysis of variance with 95% confidence interval showed that the lids that were produced with a greater total tin layer (5.6 g m?2), with normal cure (200 °C) and without scratches had a lower occurrence of the problem. The analyses also showed that the use of filling temperatures lower than 40 °C decreased the presence of black spots.  相似文献   
46.
A new software for prediction of femoral neck fractures   总被引:2,自引:0,他引:2  
Femoral neck fractures are an important clinical, social and economic problem. Even if many different attempts have been carried out to improve the accuracy predicting the fracture risk, it was demonstrated in retrospective studies that the standard clinical protocol achieves an accuracy of about 65%. A new procedure was developed including for the prediction not only bone mineral density but also geometric and femoral strength information and achieving an accuracy of about 80% in a previous retrospective study. Aim of the present work was to re-engineer research-based procedures and develop a real-time software for the prediction of the risk for femoral fracture. The result was efficient, repeatable and easy to use software for the evaluation of the femoral neck fracture risk to be inserted in the daily clinical practice providing a useful tool for the improvement of fracture prediction.  相似文献   
47.

Will affective aspects of reasoning become a major component of Artificial Intelligent Agencies or should the increasing number of initiatives in this domain be considered as a short lived interest that will be abandoned in favor of new topics?  相似文献   
48.
The purpose of the current study was to test the differential impact of two forms of metacognitive prompts on knowledge acquisition and application during simulation-based training. Participants in the experimental conditions were prompted to construct sentences by connecting declarative words (Words Group) or conceptual phrases (Phrases Group) related to the training material from two columns. Performance was then compared across conditions during an assessment scenario that did not include prompting. Overall, results provide support for the effectiveness of metacognitive prompting generally, when compared to the Control Group that did not receive prompting. Further, some support was found for providing word-based prompts over more conceptual phrase-based prompts, suggesting that the phrases may have distracted or overloaded learners. Implications for further investigation into the effects of different types of metacognitive support are discussed.  相似文献   
49.
In this paper, we describe how agents can deceive within a probabilistic framework for representing their mental state: in doing so, we challenge the so-called sincerity assumption in Human–Computer interaction (HCI) and multi-agent systems (MAS). We distinguish deception from its special case of lie and characterize different forms of deception, by identifying several criteria for distinguishing among them. In particular, we propose a model of information impact on the Receiver's mind. As the message Sender must plan its strategy by considering the Receiver's criteria for believing, we also discuss some of these criteria, like content plausibility, source informativity, and information safety. We apply this model to a simplified version of Turing's Imitation Game and describe how we implemented a Simulator of deceptive strategies that we called Mouth of Truth . We conclude the paper by describing an evaluation study that enabled us to verify the validity of our method and to revise it in part.  相似文献   
50.
The non-orthotopic expression of olfactory receptors (ORs) includes the male reproductive system, and in particular spermatozoa; their active ligands could be essential to sperm chemotaxis and chemical sperm–oocyte communication. OR51E2 expression has been previously reported on sperm cells’ surface. It has been demonstrated in different cellular models that olfactory receptor 51E2 (OR51E2) binds volatile short-chain fatty acids (SCFAs) as specific ligands. In the present research, we make use of Western blot, confocal microscopy colocalization analysis, and the calcium-release assay to demonstrate the activation of sperm cells through OR51E2 upon SCFAs stimulus. Moreover, we perform a novel modified swim-up assay to study the involvement of OR51E2/SCFAs in sperm migration. Taking advantage of computer-assisted sperm analysis (CASA system), we determine the kinematics parameters of sperm cells migrating towards SCFAs-enriched medium, revealing that these ligands are able to promote a more linear sperm-cell orientation. Finally, we obtain SCFAs by mass spectrometry in cervico-vaginal mucus and show for the first time that a direct incubation between cervical mucus and sperm cells could promote their activation. This study can shed light on the possible function of chemosensory receptors in successful reproduction activity, laying the foundation for the development of new strategies for the treatment of infertile individuals.  相似文献   
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