Translocase of outer mitochondrial membrane 40 (TOMM40) is located in the outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines.

The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available Indelligent or ShiftDetector programs, which do not search reference sequences. However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such asβ-defensin 4 (DEFB4) and its paralogHSPDP3.

Brain-specific angiogenesis inhibitor 1 (BAI1)-associated protein 2-like 1 (BAIAP2L1), also known as insulin receptor tyrosine kinase substrate (IRTKS), is involved in plasma membrane protrusion and actin formation during cell morphogenesis and migration. BAIAP2L1 is recently reported to promote cell proliferation through activation of the EGFR-ERK pathway in hepatocellular carcinoma. In this study, we report the first comprehensive study of BAIAP2L1 upregulation in human ovarian cancer. Upregulation of BAIAP2L1 in ovarian tumors was first found during RNA screening and confirmed by immunohistochemical studies on ovarian cancers and other cancer types. Significant upregulation of BAIAP2L1 in ovarian cancer was validated by analyzing multiple independent cohorts in publicly available data sets. Furthermore, BAIAP2L1 protein expression in metastatic lesions was higher than the corresponding primary tumors. Functional assays in ovarian cancer cells revealed that BAIAP2L1 is involved in promoting cell proliferation and avoiding apoptosis. In conclusion, results of this study not only indicate that BAIAP2L1 can be used as a biomarker for human ovarian cancer but also reveal its role in cancer biology. Further elucidation of the role of BAIAP2L1 in context of the insulin receptor signaling pathways of cancer cells is warranted for developing cancer therapeutics by targeting cancer-specific metabolism.

Background: Over the past decade, gene expression microarray studies have greatly expanded our knowledge of genetic mechanisms of human diseases. Meta-analysis of substantial amounts of accumulated data, by integrating valuable information from multiple studies, is becoming more important in microarray research. However, collecting data of special interest from public microarray repositories often present major practical problems. Moreover, including low-quality data may significantly reduce meta-analysis efficiency. Results: M²DB is a human curated microarray database designed for easy querying, based on clinical information and for interactive retrieval of either raw or uniformly pre-processed data, along with a set of quality-control metrics. The database contains more than 10,000 previously published Affymetrix GeneChip arrays, performed using human clinical specimens. M²DB allows online querying according to a flexible combination of five clinical annotations describing disease state and sampling location. These annotations were manually curated by controlled vocabularies, based on information obtained from GEO, ArrayExpress, and published papers. For array-based assessment control, the online query provides sets of QC metrics, generated using three available QC algorithms. Arrays with poor data quality can easily be excluded from the query interface. The query provides values from two algorithms for gene-based filtering, and raw data and three kinds of pre-processed data for downloading. Conclusion: M²DB utilizes a user-friendly interface for QC parameters, sample clinical annotations, and data formats to help users obtain clinical metadata. This database provides a lower entry threshold and an integrated process of meta-analysis. We hope that this research will promote further evolution of microarray meta-analysis.

To analyze the clinical application of endoscope with narrow-band imaging (NBI) system in detecting high-grade dysplasia, carcinoma in situ, and carcinoma in oral erythroplakia. The demographic, histopathological data, and NBI vasculature architectures of patients receiving surgical intervention for oral erythroplakia were retrospectively reviewed and analyzed statistically. A total of 72 patients, including 66 males and 6 females, with mean age of 54.6 ± 11.2 years, were enrolled. The odds ratio of detecting high-grade dysplasia, carcinoma in situ, and carcinoma by twisted elongated morphology and destructive pattern of intraepithelial microvasculature was 15.46 (confidence interval 95 %: 3.81–72.84), and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80.95 %, 78.43 %, 60.71 %, 90.91 %, and 79.17 %, respectively, which were significantly better than other two established NBI criteria (p < 0.001). Twisted, elongated, and destructive patterns of intraepithelial papillary capillary loop of NBI images are indicators for high-grade dysplasia, carcinoma in situ, and invasive carcinoma in oral erythroplakia.

Microarray analyses of transcriptomes have been used to characterize mesenchymal stem cells (MSCs) of various origins. MicroRNAs (miRNAs) are short, nonprotein-coding RNAs involved in post-transcriptional gene inhibition in a variety of tissues, including cancer cells and MSCs. This study has integrated the use of miRNA and mRNA expression profiles to analyze human MSCs derived from Wharton's jelly (WJ) of the umbilical cord, milk teeth (MT), and adult wisdom teeth (AT). Because both miRNA and mRNA expression in MT and AT MSCs were so similar, they were combined together as tooth MSCs for comparison with WJ MSCs. Twenty-five genes that were up-regulated in tooth MSCs and 41 genes that were up-regulated in WJ MSCs were identified by cross-correlating miRNA and mRNA profiles. Functional network analysis show that tooth MSCs signature genes, represented by SATB2 and TNFRSF11B, are involved in ossification, bone development, and actin cytoskeleton organization. In addition, 2 upregulated genes of tooth MSCs—NEDD4 and EMP1—have been shown to be involved in neuroectodermal differentiation. The signature genes of WJ MSCs, represented by KAL1 and PAPPA, are involved in tissue development, regulation of cell differentiation, and bone morphogenetic protein signaling pathways. In conclusion, the combined interrogation of miRNA and mRNA expression profiles in this study proved useful in extracting reliable results from a genome-wide comparison of multiple types of MSCs. Subsequent functional network analysis provided further functional insights about these MSCs.