Pan-cancer analysis of iron metabolic landscape across the Cancer Genome Atlas.

Iron is an essential metal ion in the human body and usually dysregulated in cancers. However, a comprehensive overview of the iron-related genes and their clinical relevance in cancer is lacking. In this study, we utilized the expression profiling, proteomics, and epigenetics from the Cancer Genome Atlas database to systematically characterized the alterations of iron-related genes. There were multiple iron-related genes with dysregulation across 14 cancers and some of these ectopic changes may be associated with aberrant DNA methylation. Meanwhile, a variety of genes were significantly associated with patient survival, especially in kidney renal clear cell carcinoma. Then differentially expressed genes were validated in clinical samples. Finally, we found deferoxamine and erastin could inhibit proliferation in various tumor cells and influence the expression of several iron-related genes. Overall, our study provides a comprehensive analysis of iron metabolism across cancers and highlights the potential treatment of iron targeted therapies for cancers.

[FOXO3a signaling pathway in prostate cancer: Progress in studies].

FOXO3a is an important member of the FOXO subfamily of Forkhead transcription factors, which plays an important role in promoting cell apoptosis, inducing cell cycle arrest, inhibiting cell proliferation and suppressing tumor metastasis through phosphorylation, ubiquitination-mediated degradation and microRNA. Studies show that upregulated expression of FOXO3a can inhibit the growth of PCa cells. This review summarizes the advances in the studies of the FOXO3a signaling pathway in PCa, aiming to provide some new ideas on the clinical diagnosis and targeted therapy of the malignancy.

C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis.

Human C-reactive protein (CRP) is a serum-soluble pattern recognition receptor that serves as a marker of inflammation and directly contributes to innate immunity. In this study, we show that human CRP also directly contributes to adaptive immunity, that is, native CRP binds specifically to human Jurkat T cells and to mouse naive CD4(+) T cells and modulates their Th1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naive CD4(+) T cells. In vivo for human CRP transgenic compared with wild-type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover, in both CRP transgenic mice and in wild-type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble pattern recognition receptor to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.

Monomeric C-reactive protein evokes TCR Signaling-dependent bystander activation of CD4+ T cells.

Bystander activation of T cells is defined as induction of effector responses by innate cytokines in the absence of cognate antigens and independent of T cell receptor (TCR) signaling. Here we show that C-reactive protein (CRP), a soluble pattern-recognition receptor assembled noncovalently by five identical subunits, can instead trigger bystander activation of CD4 + T cells by evoking allosteric activation and spontaneous signaling of TCR in the absence of cognate antigens. The actions of CRP depend on pattern ligand-binding induced conformational changes that result in the generation of monomeric CRP (mCRP). mCRP binds cholesterol in plasma membranes of CD4 + T cells, thereby shifting the conformational equilibrium of TCR to the cholesterol-unbound, primed state. The spontaneous signaling of primed TCR leads to productive effector responses manifested by upregulation of surface activation markers and release of IFN-γ. Our results thus identify a novel mode of bystander T cell activation triggered by allosteric TCR signaling, and reveal an interesting paradigm wherein innate immune recognition of CRP transforms it to a direct activator that evokes immediate adaptive immune responses.

Immune Cell Landscape in Gastric Cancer.

BACKGROUND: The tumor-infiltrating immune cells are closely associated with the prognosis of gastric cancer (GC). This article is aimed at determining the composition change of immune cells and immune regulatory factors in GC and normal tissues, depicting their prognosis value in GC, and revealing the relationship between them and GC clinical parameters. METHODS: We used CIBERSORT to calculate the proportion of 22 immune cells in the GC or normal tissues; a t-test was applied to assess the expression difference of immune cells and immune regulatory factors in normal and GC tissues. The relationship of the immune cells, immune regulatory factors, and GC patients' clinical characteristics was assessed by univariate analysis. RESULTS: In this study, we found that the proportion of macrophages increased, while plasma cells and monocytes decreased in GC tissues. In these immune fractions, Tregs and naïve B cells were found to be correlated with GC patients' prognosis. Interestingly, the expression of immune regulatory factors was ambiguous with their classical function in GC tissues. For example, TIM-3, FOXP3, and CMTM6 were overexpressed, while CD27 and PD-1 were underexpressed in GC tissues. We also found that IDO1, PD-1, TIGIT, and TIM-3 were highly expressed in high-grade GC tissues, the HERC2 expression level was related to patients' gender, and the TIGIT expression level was sensitive to targeted therapy. Furthermore, our results suggested that the infiltration of Tregs and naive B cells was strongly correlated with the T stage, radiation therapy, targeted molecular therapy, and the expression levels of TIM-3 and FOXP3 in GC. CONCLUSION: The expression pattern of tumor-infiltrating immune cells and immune regulatory factors was systematically depicted in the GC tumor microenvironment, indicating that individualized treatment based on the tumor-infiltrating immune cells and immune regulatory factors may be beneficial to GC patients.

Evaluation of the genetic diversity and population structure of Gasterophilus pecorum in Xinjiang Province, China, using fluorescent microsatellites (SSR) markers.

The genetic diversity of Gasterophilus pecorum populations consisting of 192 individuals sampled from Przewalski's horses (Equus ferus przewalskii) in Xinjiang Province, China, was evaluated using 12 microsatellite loci. The genetic variability within populations and genetic differentiation among populations were estimated. A total of 163 alleles were detected and the average value of observed number of alleles at each locus ranged from 7 to 19 (average 13.5625). The expected heterozygosity (He) varied from 0.5933 (GP361) to 0.9208 (GP253) and averaged 0.8426. The effective number of alleles (Ne) of the simple sequence repeat (SSR) markers was 7.1756, and it ranged from 2.4430 to 11.5214. The polymorphism information content (PIC) ranged from 0.5643 (GP361) to 0.9053 (GP253) (average 0.8119). The average Shannon's information index (I) was 2.1272. Parameters of genetic diversity (Ht, Hs and Gst) and F-statistic (Fis, Fit and Fst) were estimated. The mean of total gene diversity (Ht = 0.8798) and the average interspecific genetic diversity (Dst = 0.0110) showed that G. pecorum had a relatively high level of genetic variation, which was mainly within populations. The Fixation indices as Fst ranged from 0.0029 to 0.0950, and the Number of per generation migrants (Nm) among the populations varied from 2.3814 to 85.9745. These results indicate that the heterozygosity and genetic diversity of the G. pecorum populations were very high and that gene exchange was frequent. Correlation analyses demonstrated that the number of alleles and genetic diversity of the populations were not significantly different (p = 0.2). Unweighted Pair Group Method with Arithmetic mean (UPGMA) clustering analyses revealed a genetic similarity of 0.0671 - 0.1118. Analysis of molecular variance (AMOVA) demonstrated that the percentage of variation in the intrapopulation was small (0.67%) and the genetic variation in the G. pecorum populations was mainly exist within the species. An understanding of population genetic structure is not only crucial for assessing the actions and interactions of evolutionary forces in natural populations but also helps elucidate parasitic strategies in G. pecorum.

The incidence and species composition of Gasterophilus (Diptera, Gasterophilidae) causing equine myiasis in northern Xinjiang, China.

A survey was conducted on the detection of the larval Gasterophilus species in 90 equines via necropsy or after administering oral ivermectin in Xinjian, China, from 2008 to 2013. All 90 (100%) equines were infested by larval Gasterophilus, and 3723second instar larvae (L2) and 63,778 third instar larvae (L3) were collected from faecal samples and the digestive tract, a ratio of L2:L3=1:17. Over 84.45% of the animals contained ≤1500 larvae and 7.78% had >2000 larvae. The highest totals of L2 and L 3 larvae in any one animal were 1208 in Mongolian wild ass (Equus hemionus hemionus), 2491 in Przewalski's horse (Equus ferus przewalskii), and 1785 in the domestic horse (Equus ferus caballus). Six species of Gasterophilus were identified, with the following proportions of overall parasite abundance: Gasterophilus pecorum 88.94%, Gasterophilus nigricornis 4.94%, Gasterophilus nasalis 3.93%, Gasterophilus haemorrhoidalis 1.91%, Gasterophilus intestinalis 0.19%, and Gasterophilus inermis 0.087%. A majority of equines (n=32, 35.57%) was infested with five Gasterophilus species, while 29 animals (32.22%) harboured four species, 13 animals (14.44%) had six, 12 animals (13.33%) had three, three (3.33%) had two, and one (1.11%) had only one species. The percentage of Przewalski's horses infested was higher than local domestic horse or Mongolian wild ass.

Oviposition site selection by Gasterophilus pecorum (Diptera: Gasterophilidae) in its habitat in Kalamaili Nature Reserve, Xinjiang, China.

Oviposition site selection is an important aspect of the behavioural ecology of insects. A comparison of the habitats used by a species enhances our understanding of their adaptation to altered environments. We collected data on the oviposition behaviours of Gasterophilus pecorum (Diptera: Gasterophilidae) in its habitat in Kalamaili Nature Reserve (KNR), Xinjiang, China between March and October 2014. We found 91 quadrats were used by G. pecorum for oviposition. Examining 13 ecological factors using the t-test, chi-square test, and principal component analysis showed that G. pecorum's oviposition habitat was preferentially on slopes with inclinations of 10-30° that were semi-sunny, semi-cloudy slopes, in positions high or low on the slopes, with preferences for total plants lower than 10% and Stipa capillata coverage lower than 10% on the low slopes, but Ceratoides latens coverage on the high and intermediate slopes, when the numbers of plant species and families were lower than five. G. pecorum often selected sites at a distance < 2000 m from a water source and average altitude 900-1000 m. The oviposition site selection by G. pecorum may be correlated with the behaviour of Przewalski's horses (Equus ferus przewalskii), and water and food resources may strongly influence oviposition site selection, as Przewalski's horses rest and forage in these areas.

Mutations of C-reactive protein (CRP) -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk.

C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.