Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here IntroductionChronic inflammation, a "promoting force" in the tumor microenvironment, has long been known to be commonly braided with the initiation, promotion, and progression of tumorigenesis. [1][2][3][4][5] To date, however, it is still incompletely understood how the inflammation in the tumor microenvironment is orchestrated by inflammatory cells. Recently, mast cells were highlighted as not only a major participator but also an important regulator of inflammation, 6,7 and their accumulation in tumors has also been well documented, [8][9][10][11][12][13] implying that mast cells may possibly play an important role in orchestrating the inflammation in tumors.The tumor microenvironment is regarded as a "smoldering" inflammation site in which a lot of cytokines, chemokines, and enzymes mediate the inflammatory process and drive malignant progression. 14,15 Among them, TNF-␣, IL-6, VEGF, iNOS, Cox-2, and MMP-9 are of particular interest. [15][16][17][18] Coincidentally, all of them can be produced by mast cells. However, the tumor microenvironment is also characterized by its immunoediting from immunosurveillance to immunosuppression. 19 Mast cells have been found to play a critical role in the suppression of immune reactions. 20 They not only produce inhibitory cytokine IL-10, 21 but they also are essential for the immune tolerance mediated by regulatory T (Treg) cells. 22 Thus, mast cell infiltration into tumor may possibly remodel tumor microenvironment and profoundly influence tumor behavior by participating and regulating inflammatory and immune reactions. However, although some studies have shown that mast cells promote tumor angiogenesis and tumor growth because of their properties as inflammatory cells, [23][24][25] the roles of mast cells in tumor progression have been incompletely understood so far. Several key questions remain unclear, especially how mast cells are recruited into the tumor site and whether they can remodel the tumor microenvironment.Mast cell migration to the tumor site and the following activation may be the prerequisite for their promoting effect on tumors. In this regard, stem cell factor (SCF) is possibly involved, because SCF triggers the c-Kit signaling pathway for the differentiation, migration, maturation, and survival of mast cells. 26 In the present study, we investigated the relation of mast cells and SCF in tumor progression and showed that SCF recruited and activated mast cells, the activated mast cells remodeled the tumor microenvironment by intensifying inflammation and immunosuppression, the tumor cell NF-B and AP-1 activities were augmented, and the suppression of T cells and natural killer (NK) cells was exacerbated in such remodeled microenvironments. These findings provide a new insight into the role of mast cells in tumors and the relati...

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.

Background: In this study, the association between human papillomavirus (HPV) infection and related cervical intraepithelial neoplasia (CIN) or cervical cancer and vaginal microbiome was evaluated in Chinese cohorts. Methods: The vaginal bacterial composition of five groups, HPV-infected women without CINs (HPV, n = 78), women with low-grade squamous intraepithelial lesions (LSIL, n = 51), women with high-grade squamous intraepithelial lesions (HSIL, n = 23), women with invasive cervical cancer (Cancer, n = 9) and healthy women without HPV infection (Normal, n = 68), was characterized by deep sequencing of barcoded 16S rRNA gene fragments (V3-4) using Illumina MiSeq. Results: HPV infection increased vaginal bacterial richness and diversity regardless of the status of CINs. The vaginal bacterial richness and diversity were further augmented in women with cervical cancer. Lactobacillus was the most abundant genus in all groups. HPV infection had a negative influence on the abundances of Lactobacillus, Gardnerella and Atopobium. Accordingly, HPV infection increased the relative abundance of Prevotella, Bacillus, Anaerococcus, Sneathia, Megasphaera, Streptococcus and Anaerococcus. The increased proportions of Bacillus, Anaerococcus and the reduced abundance of Gradnerella vaginalis were probably related with the progression of CINs severity. HPV infection without CINs or cancerous lesions was strongly associated with Megasphaera. The most abundant bacterium in the LSIL group was Prevotella amnii. However, Prevotella timonensis, Shuttleworthia and Streptococcaceae at the family level were three taxa related to HSIL. Furthermore, more taxa were associated with the Cancer group including Bacillus, Sneathia, Acidovorax, Oceanobacillus profundus, Fusobacterium, Veillonellaceae at the family level, Anaerococcus and Porphyromonas uenonis. Samples in the Normal group were mostly assigned to CST III. HPV infection converted the vaginal bacterial community structure from CST III to CST IV. Furthermore, the proportions of CST IV were gradually augmented with the progression of the severity of CINs.