Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed at developing alncRNA signature to improve prognosis prediction of gastric cancer (GC).

Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients' TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.

The Uyghur population has experienced extensive interaction with European and Eastern Asian populations historically. A set of high-resolution genetic markers could be useful to infer the genetic relationships between the Uyghur population and European and Asian populations. In this study we typed 100 unrelated Uyghur males living in southern Xinjiang at 26 Y-STR loci. Using the high-resolution 26 Y-STR loci system, we investigated genetic and phylogenetic relationship between the Uyghur population and 23 reference European or Asian populations. We found that the Uyghur population exhibited a genetic admixture of Eastern Asian and European populations, and had a slightly closer relationship with the selected European populations than the Eastern Asian populations. We also demonstrated that the 26 Y-STR loci system was potentially useful in forensic sciences because it has a large power of discrimination and rarely exhibits common haplotypes. However, ancestry inference of Uyghur samples could be challenging due to the admixed nature of the population.

Early diagnosis and treatment in pancreatic ductal adenocarcinoma (PDAC) is still a challenge worldwide. The poor survival of PDAC patients mainly due to early metastasis when first diagnosed and lack of prognostic biomarker. Ribosomal protein L15 (RPL15), an RNA-binding protein, is a component of ribosomal 60S subunit. It was reported that RPL15 is dysregulated in various type of cancers. However, little is known about the role of RPL15 in PDAC carcinogenesis and progression. Herein, we clarified RPL15 expression status may serve as an independent prognostic biomarker in three independent PDAC patient cohorts. We found that RPL15 was dramatically decreased in PDAC tissues and cell lines. The high expression of RPL15 was inversely correlated with TNM stage, histological differentiation, T classification and vascular invasion. Low expression of RPL15 was significantly associated with poor overall survival of PDAC patients. Furthermore, we demonstrated that the reduction of RPL15 may promote invasion ability of pancreatic cell by inducing EMT process. In conclusion, decreased RPL15 expression is associated with invasiveness of PDAC cells, and RPL15 expression status may serve as a reliable prognostic biomarker in PDAC patients.

Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated.

The 5'-AMP-activated protein kinase (AMPK) behaves as a fuel sensor in glucose and lipid metabolism. We sequenced exon 1 and flanking regions of the gene encoding for the gamma2 subunit of AMPK (AMPKgamma2) and identified two novel common polymorphisms at position -26 and IVS1+43. We then studied these two polymorphisms in relation to plasma glucose, insulin resistance, beta-cell function, and serum lipids in 290 Han Chinese undergoing an oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test. The -26C/T and IVS1+43C/T polymorphisms were in tight linkage disequilibrium (P=0.0002). In adjusted categorical analyses, the -26TT genotype tended to be associated with a higher risk of type 2 diabetes (odds ratio 4.52, P=0.07). The adjusted continuous analyses were confirmatory. -26TT subjects, compared with -26C allele carriers, had higher concentrations of plasma glucose, both fasting (7.3 vs. 6.1 mmol/L, P=0.02) and after oral glucose loading (area under the curve for glucose, 1984 vs. 1596 minmmol/L, P=0.002), and had lower acute insulin response to glucose (143 vs. 404, P=0.0005) and disposition index (151 vs. 459, P=0.008). In further adjusted analyses, we observed that IVS1+43TT subjects, compared with IVS1+43C allele carriers, had significantly higher serum concentrations of triglycerides (4.20 vs. 2.00 mmol/L, P<0.0001) and total cholesterol (5.88 vs. 4.99 mmol/L, P=0.01). In conclusion, in Chinese, the AMPKgamma2 polymorphisms might be associated with glucose and lipid metabolism.

Current studies indicate that long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers and implicated with prognosis in gastric cancer (GC). We intended to generate a multi-lncRNA signature to improve prognostic prediction of GC. By analyzing ten paired GC and adjacent normal mucosa tissues, 339 differentially expressed lncRNAs were identified as the candidate prognostic biomarkers in GC. Then we used LASSO Cox regression method to build a 12-lncRNA signature and validated it in another independent GEO dataset. An innovative 12-lncRNA signature was established, and it was significantly associated with the disease free survival (DFS) in the training dataset. By applying the 12-lncRNA signature, the training cohort patients could be categorized into high-risk or low-risk subgroup with significantly different DFS (HR = 4.52, 95%CI= 2.49-8.20, P < 0.0001). Similar results were obtained in another independent GEO dataset (HR=1.58, 95%CI=1.05 - 2.38, P=0.0270). Further analysis showed that the prognostic value of this 12-lncRNA signature was independent of AJCC stage and postoperative chemotherapy. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of combined model reached 0.869. Additionally, a well-performed nomogram was constructed for clinicians. Moreover, single-sample gene-set enrichment analysis (ssGSEA) showed that a group of pathways related to drug resistance and cancer metastasis significantly enriched in the high risk patients. A useful innovative 12-lncRNA signature was established for prognostic evaluation of GC. It might complement clinicopathological features and facilitate personalized management of GC.

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.

The abnormal expression of microRNAs (miRNAs) in colorectal cancer (CRC) progression has been widely investigated. It was reported that the same hairpin RNA structure could generate mature products from each strand, termed 5p and 3p, which binds different target mRNAs. Here, we explored the expression, functions, and mechanisms of miR-514b-3p and miR-514b-5p in CRC cells and tissues. We found that miR-514b-3p was significantly down-regulated in CRC samples, and the ratio of miR-514b-3p/miR-514b-5p increased from advanced CRC, early CRC to matched normal colorectal tissues. Follow-up functional experiments illustrated that miR-514b-3p and miR-514b-5p had distinct effects through interacting with different target genes: MiR-514b-3p reduced CRC cell migration, invasion and drug resistance through increasing epithelial marker and decreasing mesenchymal marker expressions, conversely, miR-514b-5p exerted its pro-metastatic properties in CRC by promoting EMT progression. MiR-514b-3p overexpressing CRC cells developed tumors more slowly in mice compared with control cells, however, miR-514b-5p accelerated tumor metastasis. Overall, our data indicated that though miR-514b-3p and miR-514b-5p were transcribed from the same RNA hairpin, each microRNA has distinct effect on CRC metastasis.

Recent genetic evidence has linked WNT downstream mutations to fat distribution. However, the roles of WNTs in human obesity remain unclear. Here, the authors screen all Wnt-related paracrine factors in 1994 obese cases and 2161 controls using whole-exome sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. RSPO1 is predominantly expressed in visceral fat, primarily in the fibroblast cluster, and is increased with adiposity. Mice overexpressing human RSPO1 in adipose tissues develop obesity under a high-fat diet (HFD) due to reduced brown/beige fat thermogenesis. In contrast, Rspo1 ablation resists HFD-induced adiposity by increasing thermogenesis. Mechanistically, RSPO1 overexpression or administration significantly inhibits adipocyte mitochondrial respiration and thermogenesis via LGR4-Wnt/β-catenin signaling pathway. Importantly, humanized knockin mice carrying the hotspot mutation (p.R219W) display suppressed thermogenesis and recapitulate the adiposity feature of obese carriers. The mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, leading to excessive RSPO1 release that activates LGR4-Wnt/β-catenin signaling and attenuates thermogenic capacity in differentiated beige adipocytes. Therefore, these findings identify that gain-of-function mutations and excessive expression of RSPO1, acting as a paracrine Wnt activator, suppress fat thermogenesis and contribute to obesity in humans.

The aim of this study was to observe the effectiveness of botulinum toxin type A (BTA) in the treatment of intermittent exotropia (IXT) in children compared with strabismus surgery.

Fusobacterium nucleatum (F. nucleatum) is enriched in colorectal cancer (CRC) tissues and a high amount of F. nucleatum was associated with an immunosuppressive tumor environment. PD-L1 is an important immune checkpoint expressed on tumor cells and promotes tumor immune escape. Whether PD-L1 is regulated by F. nucleatum is still unclear. We demonstrated that F. nucleatum promoted CRC progression and upregulated PD-L1 protein expression in CRC cell lines. Combined m6A-seq and RNA-seq identified m6A-modified IFIT1 mediating F. nucleatum induced PD-L1 upregulation. IFIT1 mRNA was modified with m6A modifications in 3'UTR and the m6A levels were altered by F. nucleatum treatment. Our results also indicated that IFIT1 served as a potential oncogene in CRC and regulated PD-L1 protein levels through altering PD-L1 ubiquitination. Clinical CRC data confirmed the correlation among F. nucleatum abundance, IFIT1 and PD-L1 expressions. Our work highlighted the function of F. nucleatum in stimulating PD-L1 expression through m6A-modified IFIT1 and provided new aspects for understanding F. nucleatum mediated immune escape.

Maladaptation of host-microbiota metabolic interplay plays a critical role in colorectal cancer initiation. Here, through a combination of single-cell transcriptomics, microbiome profiling, metabonomics, and clinical analysis on colorectal adenoma and carcinoma tissues, we demonstrate that host's urea cycle metabolism is significantly activated during colorectal tumorigenesis, accompanied by the absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium, and the overabundance of pathogenic bacteria lacking ureolytic function. Urea could enter into macrophages, inhibit the binding efficiency of p-STAT1 to SAT1 promotor region, and further skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines. Treating a murine model using urea cycle inhibitors or Bifidobacterium-based supplements could mitigate urea-mediated tumorigenesis. Collectively, this study highlights the utility of urea cycle inhibitors or therapeutically manipulating microbial composition using probiotics to prevent colorectal cancer.

MicroRNAs (miRNAs) are involved in the regulation of adiposity, but functional studies have yielded inconclusive results. Examining the associations of circulating miRNAs levels with obesity and insulin sensitivity in humans may lead to improved insights.

To investigate the typing for human leukocyte antigen (HLA) class I in Chinese patients with type 1 diabetes as a complement screening for HLA class II.

A small percentage of retinal ganglion cells (RGCs) express melanopsin and are intrinsically photosensitive (ipRGCs). Whether light can affect the development of ipRGCs is not clear. In the rat retina, we found constant light exposure during the first postnatal week significantly increased the number of melanopsin immunopositive ipRGCs. This increase was durable and specific for melanopsin immunopositive ipRGCs. BrdU labeling showed no proliferation of the melanopsin immunopositive ipRGCs during constant light exposure. Retrograde labeling from the superior colliculus showed that no other types of RGCs were induced to express melanopsin. Light exposure was effective in increasing melanopsin immunopositive ipRGCs only when it coincided with the apoptotic phase of RGC development. However, daily intravitreous injection of tetrodotoxin, blocking action potentials, abolished the light induced increase of melanopsin immunopositive ipRGCs. These findings indicate that early light exposure can increase the number of melanopsin immunopositive ipRGCs through a process dependent on intrinsic photosensitive spiking activity. Furthermore, the increase of melanopsin immunopositive ipRGCs is potentially induced by apoptosis suppression in ipRGCs or enhanced expression of melanopsin.

Abnormalities in the JAK2/STAT3 pathway are involved in the pathogenesis of colorectal cancer (CRC), including apoptosis. However, the exact mechanism by which dysregulated JAK2/STAT3 signalling contributes to the apoptosis has not been clarified. To investigate the role of both JAK2 and STAT3 in the mechanism underlying CRC apoptosis, we inhibited JAK2 with AG490 and depleted STAT3 with a small interfering RNA. Our data showed that inhibition of JAK2/STAT3 signalling induced CRC cellular apoptosis via modulating the Bcl-2 gene family, promoting the loss of mitochondrial transmembrane potential (Δψm) and the increase of reactive oxygen species. In addition, our results demonstrated that the translocation of cytochrome c (Cyt c), caspase activation and cleavage of poly (ADP-ribose) polymerase (PARP) were present in apoptotic CRC cells after down-regulation of JAK2/STAT3 signalling. Moreover, inhibition of JAK2/STAT3 signalling suppressed CRC xenograft tumour growth. We found that JAK2/STAT3 target genes were decreased; meanwhile caspase cascade was activated in xenograft tumours. Our findings illustrated the biological significance of JAK2/STAT3 signalling in CRC apoptosis, and provided novel evidence that inhibition of JAK2/STAT3 induced apoptosis via the mitochondrial apoptotic pathway. Therefore, JAK2/STAT3 signalling may be a potential target for therapy of CRC.

The trafficking protein particle complex 4 (TRAPPC4) is implicated in vesicle-mediated transport, but its association with disease has rarely been reported. We explored its potential interaction with ERK2, part of the ERK1/2 complex in the Extracellular Signal-regulated Kinase/ Mitogen-activated Protein Kinase (ERK-MAPK) pathway, by a yeast two-hybrid screen and confirmed by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down. Further investigation found that when TRAPPC4 was depleted, activated ERK1/2 specifically decreased in the nucleus, which was accompanied with cell growth suppression and apoptosis in colorectal cancer (CRC) cells. Overexpression of TRAPPC4 promoted cell viability and caused activated ERK1/2 to increase overall, but especially in the nucleus. TRAPPC4 was expressed more highly in the nucleus of CRC cells than in normal colonic epithelium or adenoma which corresponded with nuclear staining of pERK1/2. We demonstrate here that TRAPPC4 may regulate cell proliferation and apoptosis in CRC by interaction with ERK2 and subsequently phosphorylating ERK1/2 as well as modulating the subcellular location of pERK1/2 to activate the relevant signaling pathway.

Due to the increased application of titanium dioxide nanoparticles (TiO₂ NPs) in the food industry and daily life, their potential toxic effects in humans and animals have been investigated. However, very few studies have focused on testicular oxidative stress and/or apoptosis.

Currently, impacts of exposure to TiO2 nanoparticles (NPs) on the cardiovascular system are not well understood. The aim of this study was to investigate whether TiO2 NPs induce myocarditis and its underlying molecular mechanism in the cardiac inflammation in mice. Mice were exposed to TiO2 NPs for 6 months; biochemical parameters of serum and expression of Th1-related and Th2-related cytokines in the heart were investigated. The results showed that TiO2 NP exposure resulted in cardiac lesions coupling with pulmonary inflammation; increases of aspartate aminotransferase (AST), creatine kinase (CK), C-reaction protein (CRP), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH), adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) levels; and a reduction of nitric oxide (NOx) level in the serum. These were associated with increases of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, transforming growth factor-β (TGF-β), creatine kinase, CRP, adhesion molecule-1, and monocyte chemoattractant protein-1, interferon-γ (IFN-γ), signal transducers and activators of transcription (STAT)1, STAT3, or STAT6, GATA-binding domain-3, GATA-binding domain-4, endothelin-1 expression levels, and T-box expressed in T cells expression level that is the master regulator of pro-inflammatory cytokines and transcription factors in the heart. These findings imply that TiO2 NP exposure may increase the occurrence and development of cardiovascular diseases.