Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.

Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.

The Complex Network between MYC Oncogene and microRNAs in Gastric Cancer: An Overview.

Despite the advancements in cancer treatments, gastric cancer is still one of the leading causes of death worldwide. In this context, it is of great interest to discover new and more effective ways of treating this disease. Accumulated evidences have demonstrated the amplification of 8q24.21 region in gastric tumors. Furthermore, this is the region where the widely known MYC oncogene and different microRNAs are located. MYC deregulation is key in tumorigenesis in various types of tissues, once it is associated with cell proliferation, survival, and drug resistance. microRNAs are a class of noncoding RNAs that negatively regulate the protein translation, and which deregulation is related with gastric cancer development. However, little is understood about the interactions between microRNAs and MYC. Here, we overview the MYC role and its relationship with the microRNAs network in gastric cancer aiming to identify potential targets useful to be used in clinic, not only as biomarkers, but also as molecules for development of promising therapies.

CRISPR/Cas9 Genome-Editing Technology and Potential Clinical Application in Gastric Cancer.

Gastric cancer is the subject of clinical and basic studies due to its high incidence and mortality rates worldwide. Due to the diagnosis occurring in advanced stages and the classic treatment methodologies such as gastrectomy and chemotherapy, they are extremely aggressive and limit the quality of life of these patients. CRISPR/Cas9 is a tool that allows gene editing and has been used to explore the functions of genes related to gastric cancer, in addition to being used in the treatment of this neoplasm, greatly increasing our understanding of cancer genomics. In this mini-review, we seek the current status of the CRISPR/Cas9 gene-editing technology in gastric cancer research and clinical research.

Genetic and Transcriptional Analysis of 8q24.21 Cluster in Gastric Cancer.

BACKGROUND/AIM: Previous studies from our research group have shown that trisomy 8 and the amplification of the 8q24.21 region is very frequent in gastric cancer (GC). Little is known about the role of most genes located in this region. Thus, the aim of this study was to understand the possible impact of transcriptional alterations and copy number variation (CNV) of four genes located in the 8q24.21 region - FAM49B, FAM84B, GSDMC and miR-5194 - in GC. MATERIALS AND METHODS: Fifty-one to 85 matched pairs of tumoral and adjacent non-tumoral gastric tissues, from patients with primary GC, were used to analyze gene expression and CNV of the selected genes. We also included 29 H. pylori negative and gastritis negative gastric mucosa tissues from individuals without cancer obtained by endoscopy, as control samples. RESULTS: The expression of FAM49B, GSDMC and miR-5194 was higher in both tumoral and adjacent non-tumoral samples compared to the negative control. The expression of FAM84B showed no significant difference between tumoral samples and negative controls. However, the expression of FAM84B in the adjacent non-tumoral samples was higher compared to negative control and tumoral samples. Moreover, the higher expression of GSDMC was associated with T3 and T4 tumors, with tumors on stage III and IV and with advanced tumors. Higher copy numbers of FAM49B and GSDMC were associated with intestinal tumor type and with moderately or well-differentiated tumors. Higher copy number of FAM84B was associated with moderately or well-differentiated tumors. Furthermore, the expression of all four genes was positively correlated. CONCLUSION: All four genes are upregulated in GC and may play an important role in these neoplasms. GSDMC expression was associated with more aggressive tumors.

Evaluation of LAGE-1 and NY-ESO-1 expression in multiple myeloma patients to explore possible benefits of their homology for immunotherapy.

Due to the high homology between the LAGE-1 and NY-ESO-1 proteins, we hypothesized that an anti-NY-ESO-1 vaccine might elicit LAGE-1 immunity and hence may be effective in multiple myeloma (MM) patients with LAGE-1-positive/NY-ESO-1-negative tumors. Therefore, we set out to evaluate LAGE-1 and NY-ESO-1 mRNA and protein expression in MM patients in a bid to evaluate possible benefits of their homology for immunotherapy. LAGE-1 (a and b isoforms) and NY-ESO-1 mRNA expression was studied in 18 normal tissues and 50 bone marrow MM samples by RT-PCR. LAGE-1 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in 27 MM specimens using mAbs 219-510-23 and E978. Spontaneous serological immune response against both antigens was analyzed by ELISA in sera from 33 MM patients. LAGE-1 (a and b isoforms) was positive in 42% and NY-ESO-1 in 26% of the MM samples analyzed by RT-PCR. Both genes were found to be expressed in 18% of the cases, while at least one of the genes was found to be expressed in 50% of the cases. In LAGE-1 positive samples, 81% were positive for LAGE-1a and 19% were positive for both LAGE-1a and -1b. LAGE-1 and NY-ESO-1 protein expression could only be detected in two cases by IHC and there was a clear strong spontaneous antibody response to LAGE-1 and NY-ESO-1 in only one MM patient. In conclusion, LAGE-1a and NY-ESO-1 homology cannot be easily exploited in an anti-NY-ESO-1 vaccine given the low frequency of protein expression detected by IHC or serum analysis.

LINC00152 Promotes Invasion through a 3'-Hairpin Structure and Associates with Prognosis in Glioblastoma.

Long noncoding RNAs (lncRNA) are increasingly implicated in oncogenesis. Here, it is determined that LINC00152/CYTOR is upregulated in glioblastoma multiforme (GBM) and aggressive wild-type IDH1/2 grade 2/3 gliomas and upregulation associates with poor patient outcomes. LINC00152 is similarly upregulated in over 10 other cancer types and associates with a poor prognosis in 7 other cancer types. Inhibition of the mostly cytoplasmic LINC00152 decreases, and overexpression increases cellular invasion. LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT). PARIS and Ribo-seq data, together with secondary structure prediction, identified a protein-bound 121-bp stem-loop structure at the 3' end of LINC00152 whose overexpression is sufficient to increase invasion of GBM cells. Point mutations in the stem-loop suggest that stem formation in the hairpin is essential for LINC00152 function. LINC00152 has a nearly identical homolog, MIR4435-2HG, which encodes a near identical hairpin, is equally expressed in low-grade glioma (LGG) and GBM, predicts poor patient survival in these tumors, and is also reduced by LINC00152 knockdown. Together, these data reveal that LINC00152 and its homolog MIR4435-2HG associate with aggressive tumors and promote cellular invasion through a mechanism that requires the structural integrity of a hairpin structure.Implications: Frequent upregulation of the lncRNA, LINC00152, in glioblastoma and other tumor types combined with its prognostic potential and ability to promote invasion suggests LINC00152 as a potential biomarker and therapeutic target. Mol Cancer Res; 16(10); 1470-82. ©2018 AACR.

A Comprehensive Expression Analysis of Cancer Testis Antigens in Head and Neck Squamous Cell Carcinoma Revels MAGEA3/6 as a Marker for Recurrence.

Despite significant advances in the treatment of head and neck squamous cell carcinoma (HNSCC), the survival rate has not changed in the last decades. Therefore, the development of novel therapeutic strategies is pursued. Cancer-testis antigens (CTA) are strong immunogenic proteins with a tumor-restricted expression pattern, and are considered ideal targets for tumor-specific immunotherapeutic approaches. In this study, using an in silico approach, we selected, among 139 previously described CTA, candidates to be evaluated in 89 HNSCC and 20 normal mucosa samples. SPANX-CD (71.9%), MAGEB2 (44.9%), MAGEA1 (44.9%), MAGEB6 (32.6%), and CXORF48 (27.0%) were found frequently expressed in HNSCC, and over 85% of the tumors expressed at least one of these five CTAs. The mRNA positivity of CXORF48, MAGEB6, and CRISP2 presented significant associations with recognized clinical features for poor outcome. Furthermore, MAGEA3/6 positivity was associated with significantly better disease-free survival (DFS, P = 0.014), and the expression of this antigen was shown to be an independent prognostic factor for tumor recurrence. In conclusion, one of five selected CTAs is expressed in at least 85% of the HNSCCs, suggesting a possible usage as target for immunotherapeutic approaches, and the mRNA-positivity for MAGEA3/6 is shown to be an independent marker for DFS.