IBM Watson for Oncology (WFO) has begun to be used in China. In this study, concordance was examined between the treatment recommendation proposed by WFO and clinical decisions for 362 patients in our cancer center, which could reflect the differences of cancer treatment between China and the U.S. Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major causes of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. This study may have a significant effect on application of artificial intelligence systems in China.
Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct biological activities on different cell types. Our studies indicate that interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4 signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4–inducible genes. The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4–inducible genes can be regulated in a lineage-specific manner.
Synaptic dopamine levels appear to affect the in vivo binding of many D2 receptor radioligands. Thus, release of endogenous dopamine induced by administration of amphetamine decreases ligand binding, whereas subchronic dopamine depletion increases binding. This is generally thought to be due to binding competition between endogenous dopamine and the radioligands. However, the temporal dissociation between amphetamine-induced increases in dopamine, which last on the order of 2 hours as measured by microdialysis, and the prolonged decrease in ligand binding, which lasts on the order of a day, has suggested that agonist-induced D2 receptor internalization may contribute to the sustained decrease in D2 receptor binding potential seen following a dopamine surge. To test this hypothesis, we developed an in vitro system showing robust agonist-induced D2 receptor internalization following treatment with the agonist quinpirole. HEK293 cells were stably co-transfected with human D2 receptor, G-protein-coupled-receptor kinase 2 and arrestin 3. Agonist-induced D2 receptor internalization was demonstrated by fluorescence microscopy, flow cytometry and radioligand competition binding. The binding of seven antagonists and four agonists to surface and internalized receptors was measured in intact cells. All imaging ligands bound with high affinity to both surface and internalized D2 receptors. Affinity to internalized receptors was modestly lower, supporting the hypothesis that internalization would reduce binding potential measured in imaging studies performed with these ligands. However, between-ligand differences in the magnitude of the internalization-associated affinity shift only partly accounted for the data obtained in neuroimaging experiments, suggesting that mechanisms beyond competition and internalization are involved.
Psoriasis is a chronic inflammatory skin disease that severely affects patients physiologically and psychologically. The pathogenesis involving communication between psoriatic keratinocytes and infiltrated immune cells such as neutrophils remains unclear. Exosomes are emerging mediators of intercellular communication. Herein we aim to investigate the release and function of psoriatic keratinocyte exosomes, which have not been illustrated to any extent. We first isolated exosomes from both healthy and psoriasis-like keratinocytes treated with psoriatic cytokine cocktail. These exosomes were observed to be endocytosed by neutrophils. Unlike non-cytokine-treated keratinocyte exosomes, cytokine-treated keratinocyte exosomes significantly induced NETosis (the process by which neutrophils produce and release neutrophil extracellular traps) and the expressions of IL-6, IL-8, and TNFa in neutrophils. Proteomic analysis showed that cytokine-treated keratinocyte exosomes exhibited a specific protein profile with proteins enriched in immune-related pathways. We then confirmed that NF-kB and p38 MAPK signaling pathways were activated in neutrophils stimulated by cytokine-treated keratinocyte exosomes and were responsible for the expressions of proinflammatory factors mentioned above. Finally, we verified in vivo that cytokine-treated keratinocyte exosomes participated in the skin lesion development of imiquimodinduced psoriasis-like mouse model. Collectively, we reveal that the release of exosomes works as a way of keratinocyte-neutrophil communication, indicating that keratinocyte exosomes, with their specific cargoes, are therapeutic candidates for psoriasis.-
Further investigation is needed to understand the genomics and clinical characteristics of young patients with lung adenocarcinoma. In the present study, hybrid capture-based next-generation sequencing assays were used to identify targeted genetic alterations in young lung adenocarcinoma patients. Young patients with lung adenocarcinoma, aged less than 45 years, harbored a higher frequency of and genetic alterations compared with patients aged more than 46 years. Dramatically, concurrent / mutations were much more prevalent in younger patients, which had a poor response to treatment with epidermal growth factor receptor kinase inhibitor. These results reveal a distinctive genetic profile in younger patients with adenocarcinoma, which might improve the treatment of this subpopulation.
Psoriasis is a chronic inflammatory autoimmune skin disease that often occurs in rubbed areas undergoing a strong mechanical stretch, such as the elbows and knees. However, the pathologic role of mechanical tension in psoriasis remains unclear. In this study, we investigated the contribution of keratinocyte mechanical stretch to the clinical features of psoriasis. We found that keratinocyte proliferation and skin barrier-associated gene expression increased significantly after 24 hours of continuous stretching. Additionally, continuous stretching induced the production of psoriasis-associated proinflammatory cytokines, antibacterial peptides, and chemokines in primary human keratinocytes. Furthermore, we established a murine model of skin expansion by implanting a dilator into the dorsum of BALB/c mice to assess the effect of mechanical stretch on the epidermis in vivo. The dilator-implanted mice displayed prominent epidermal hyperproliferation, impaired skin barrier function, and up-regulation of psoriasis-associated cytokines in epidermal keratinocytes. Most importantly, the dilator-implanted psoriatic mice treated with imiquimod or IL-23 displayed an aggravated psoriatic phenotype compared with mice without dilator implantation. Collectively, our results suggest that mechanical stretch can exacerbate psoriatic lesions by promoting cell proliferation and amplifying the production of proinflammatory cytokines by keratinocytes. Thus, our findings provide new insights into the pathogenesis of psoriasis.
Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disease that can be life‐threatening. Gene mutations are found in some cases, but its immune pathogenesis is largely unknown. Here, we observed that the neutrophil:lymphocyte ratio in patients with GPP was higher than that in healthy controls and decreased after effective treatment. Neutrophils isolated from patients with GPP induced higher expressions of inflammatory genes including IL‐1β, IL‐36G, IL‐18, TNF‐α, and C‐X‐C motif chemokine ligands in keratinocytes than normal neutrophils did. Moreover, neutrophils from patients with GPP secreted more exosomes than controls, which were then rapidly internalized by keratinocytes, increasing the expression of these inflammatory molecules via activating NF‐κB and MAPK signaling pathways. The proteomic profiles in neutrophil exosomes further characterized functional proteins and identified olfactomedin 4 as the critical differentially expressed protein that mediates the autoimmune inflammatory responses of GPP. These results demonstrate that neutrophil exosomes have an immune‐regulatory effect on keratinocytes, which modulates immune cell migration and autoinflammation in GPP.—Shao, S., Fang, H., Zhang, J., Jiang, M., Xue, K., Ma, J., Zhang, J., Lei, J., Zhang, Y., Li, B., Yuan, X., Dang, E., Wang, G. Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes. FASEB J. 33, 6813–6828 (2019). http://www.fasebj.org
Background: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs. Methods: A total of 19 studies from 4 databases (PubMed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed with the STATA 14.0 software. We analyzed the incidences of total AEs, total SAEs and SAEs for different ALK inhibitors. Results: AEs of the ALK inhibitors occurred in almost all participants, and SAEs occurred in more than 20% of the participants. For ceritinib and brigatinib, SAEs occurred in more than 40% of the participants. Alectinib is most likely the safest of the two generations of ALK inhibitors. Generally, the ALK inhibitors showed significant lung toxicity. Conclusion: In conclusion, attention should be focused on ALK inhibitor-related SAEs, especially lung toxicity. According to this meta-analysis, alxectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when prescribing ALK inhibitors.
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