Long noncoding RNAs (lncRNA) play important roles in the tumorigenesis and progression of cancers. However, the clinical significance of lncRNAs and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) are largely unknown. Here, based on a microarray analysis, we identified 384 dysregulated lncRNAs, of which, FAM225A was one of the most upregulated lncRNAs in NPC. FAM225A significantly associated with poor survival in NPC. N(6)-Methyladenosine (m6A) was highly enriched within FAM225A and enhanced its RNA stability. FAM225A functioned as an oncogenic lncRNA that promoted NPC cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, FAM225A functioned as a competing endogenous RNA (ceRNA) for sponging miR-590-3p and miR-1275, leading to the upregulation of their target integrin b3 (ITGB3), and the activation of FAK/PI3K/Akt signaling to promote NPC cell proliferation and invasion. In summary, our study reveals a potential ceRNA regulatory pathway in which FAM225A modulates ITGB3 expression by binding to miR-590-3p and miR-1275, ultimately promoting tumorigenesis and metastasis in NPC. Significance: These findings demonstrate the clinical significance of the lncRNA FAM225A in nasopharyngeal carcinoma (NPC) and the regulatory mechanism involved in NPC development and progression, providing a novel prognostic indicator and promising therapeutic target.

The salience network (SN) serves to identify salient stimuli and to switch between the central executive network (CEN) and the default-mode network (DMN), both of which are impaired in Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI). We hypothesized that both the structural and functional organization of the SN and functional interactions between the SN and CEN/DMN are altered in normal aging and in AD/aMCI. Gray matter volume (GMV) and resting-state functional connectivity (FC) were analyzed from healthy younger (HYC) to older controls (HOC) and from HOC to aMCI and AD patients. All the SN components showed significant differences in the GMV, intranetwork FC, and internetwork FC between the HYC and HOC. Most of the SN components showed differences in the GMV between the HOC and AD and between the aMCI and AD. Compared with the HOC, AD patients exhibited significant differences in intra- and internetwork FCs of the SN, whereas aMCI patients demonstrated differences in internetwork FC of the SN. Most of the GMVs and internetwork FCs of the SN and part of the intranetwork FC of the SN were correlated with cognitive differences in older subjects. Our findings suggested that structural and functional impairments of the SN may occur as early as in normal aging and that functional disconnection between the SN and CEN/ DMN may also be associated with both normal aging and disease progression.

Abstract. Epigenetic regulation plays a significant role in gliomas. However, how methylation and long non-coding RNA (lncRNA) cooperates to regulate gliomas progression is largely unknown. In this investigation we showed that the downregulation of MEG3 expression due to hypermethylation of MEG3 was observed in gliomas tissues. Treatment of glioma cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) decreased aberrant hypermethylation of the MEG3 promoter and prevented the loss of MEG3 expression. In addition, DNMT1 was involved in MEG3 promoter methylation, and was inversely correlated with MEG3 expression in gliomas. The inhibition of DNMT1 repressed the proliferation, clone formation, and induced apoptosis in glioma cells. Importantly, the inhibition of DNMT1 contributed to the activation of p53 pathways in gliomas cells. These results suggest that DNMT1-mediated MEG3 hypermethylation caused the loss of MEG3 expression, followed by the inhibition of the p53 pathways in gliomas.

The development of transgenic technologies in monkeys is important for creating valuable animal models of human physiology so that the etiology of diseases can be studied and potential therapies for their amelioration may be developed. However, the efficiency of producing transgenic primate animals is presently very low, and there are few reports of success. We have developed an improved methodology for the production of transgenic rhesus monkeys, making use of a simian immunodeficiency virus (SIV)-based vector that encodes EGFP and a protocol for infection of early-cleavagestage embryos. We show that infection does not alter embryo development. Moreover, the timing of infection, either before or during embryonic genome activation, has no observable effect on the level and stability of transgene expression. Of 70 embryos injected with concentrated virus at the one-to two-cell stage or the four-to eight-cell stage and showing fluorescence, 30 were transferred to surrogate mothers. One transgenic fetus was obtained from a fraternal triple pregnancy. Four infant monkeys were produced from four singleton pregnancies, of which two expressed EGFP throughout the whole body. These results demonstrate the usefulness of SIV-based lentiviral vectors for the generation of transgenic monkeys and improve the efficiency of transgenic technology in nonhuman primates. lentiviral vector | transgenesis

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

CRS and HIPEC represent the standard treatment strategy for selected patients with MPM, and patients with unresectable tumors can benefit from the combined treatment of chemotherapy, radiotherapy, and immunotherapy.

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