👤 David Shieh

Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous condition caused by postzygotic mosaic activating variants in genes including FGFR1, NRAS, or KRAS. It primarily affects the skin, eyes, and central nervous system. Diagnosis is typically based on characteristic clinical features and/or molecular confirmation. Here we report a unique case of ECCL in a 12-year-old female with abdominal wall lipoma, ipsilateral lower limb overgrowth, and brachydactyly, in whom somatic mosaicism for FGFR1 was identified using resected lipomatous tissue. Imaging studies confirmed additional spinal lipomas consistent with ECCL. This report expands the phenotypic spectrum of FGFR1-ECCL and underscores the importance of tissue-based somatic testing for diagnosis. Tumor risk is also discussed. Show less

Previous reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in chromosome 10q with global developmental delay, musculoskeletal abnormalities, and dysmorphic features has not been previously reported. Genetic testing using whole exome sequencing (WES) was performed on three patients with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Sequencing reads were aligned to the human genome build GRCh37/UCSC hg19 and analysed for both sequence and copy number variants. WES identified similar interstitial deletions in the 10q21.1q21.3 locus in all three patients. The deleted region includes online Mendelian inheritance in man (OMIM)-annotated genes with clinical significance, such as This is the first report associating interstitial deletions in the 10q21.1q21.3 locus with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Our findings highlight the clinical significance of this deleted region and suggest possible mechanisms underlying the observed pathological phenotypes. Show less

Elevated expression of prothymosin α (ProT) is frequently observed in cancers, but the underlying molecular mechanism remains poorly understood. Here, we report the clinical relevance of ProT expression and its correlation with lung cancer progression. We have shown that ProT was highly expressed in early-stage lung cancer, exhibiting nuclear localization; on the contrary, a loss of nuclear ProT expression was detected in late-stage tumor specimens. Furthermore, the expression of nuclear ProT impaired lung cancer cell migration, suppressed TGF-β-induced epithelial-to-mesenchymal transition (EMT)-associated transcription factor expression, and inhibited in vivo tumor metastasis. The suppressive effect of ProT was further found to trigger Smad7 acetylation-dependent deregulation of TGF-β signaling. ProT enhanced Smad7 stability by promoting its lysine acetylation, thereby competing with the binding of Smad2 to the SNAI1, TWIST1, and ZEB1 promoters. Eventually, the binding of Smad7 in the presence of ProT resulted in reduced expression of the EMT transcription factors, leading to the inhibition of TGF-β-induced EMT and tumor metastasis. Collectively, this study unravels the role of ProT in lung cancer progression and highlights the potential of nuclear ProT as an indicator for monitoring tumor development. Show less

Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF-induced COX-2 and angiopoietin-like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX-2-derived prostaglandin E Show less

Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn't regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2 Show less

Recently, increasing numbers of long noncoding RNAs (lncRNAs), with both oncogenic and tumor-suppressive potential, have been found to be aberrantly expressed in various human cancers. However, the function of lncRNAs in hepatocellular carcinoma (HCC) progression remains largely unknown. In this study, we performed a comprehensive microarray analysis of lncRNA expression using human HCC specimens. After validation in 119 human HCC tissues, we identified a novel tumor suppressor lncRNA, CPS1 intronic transcript 1 (CPS1-IT1). To elucidate the clinical significance of CPS1-IT1 in HCC, correlations between CPS1-IT1 levels, clinical parameters, and survival outcomes were analyzed. In vitro and in vivo functional assays were also performed to dissect the potential underlying mechanisms. Expression of CPS1-IT1 was significantly decreased in 73% of HCC tissues, and patients with low CPS1-IT1 expression had poor survival outcomes. Furthermore, in vitro functional assays indicated that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities through reduced Hsp90 binding to and activation of HIF-1α, thereby suppressing the epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor suppressor role of CPS1- IT1 via decreased tumor growth and metastasis. In conclusion, lncRNA CPS1-IT1 acts as a tumor suppressor in HCC by reducing HIF-1α activation and suppressing EMT. The findings of this study establish a function for CPS1-IT1 in HCC progression and suggest its potential as a new prognostic biomarker and target for HCC therapy. Show less

Exostosin 1 (EXT1) is a glycosyltransferase that contributes to the biosynthesis of heparan sulfate proteoglycans (HSPG). Loss of ext1 function leads to the human genetic disorder hereditary multiple exostoses (HME) and inhibits development in mouse, zebrafish and Drosophila. In Xenopus, loss of maternal EXT1 leads to impaired wnt11 signaling, resulting in a loss of dorsal embryonic development (Tao et al., 2005), but the functions of zygotic ext1 have not been elucidated. In this study, morpholino oligonucleotides were used to generate a zygotic partial loss of function for ext1, in order to evaluate the requirements for ext1 function in gastrulation and paracrine signaling. Transcriptional profiling was carried out by microarray. Validation and subsequent analyses of gene expression were performed using Q-RT-PCR and in situ hybridization. Western blots were used to assess paracrine signaling pathway activity. Introduction of ext1 MO led to gastrulation defects, which were partially rescued by co-injection of ext1 mRNA. Microarray-based comparisons of gene expression in control vs. Ext1 MO embryos identified several developmentally significant genes that are dependent upon Ext1 function, including brachyury (Xbra). In addition, decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. Show less

Glycogen storage disease type Ia (GSD-Ia) patients manifest a pro-atherogenic lipid profile but are not at elevated risk for developing atherosclerosis. Serum phospholipid, which correlates positively with the scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, and apolipoprotein A-IV and E, acceptors for ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol transport, are increased in GSD-Ia mice. Importantly, sera from GSD-Ia mice are more efficient than sera from control littermates in promoting SR-BI- and ABCA1-mediated cholesterol effluxes. As the first step in reverse cholesterol transport, essential for cholesterol homeostasis, these observations provide one explanation why GSD-Ia patients are apparently protected against premature atherosclerosis. Show less

Oral squamous cell carcinoma (OSCC) is a common malignancy, the incidence of which is particularly high in some Asian countries due to the geographically linked areca quid (AQ) chewing habit. In this study, array-based comparative genomic hybridization was used to screen microdissected OSCCs for genome-wide alterations. The highest frequencies of gene gain were detected for TP63, Serpine1, FGF4/FGF3, c-Myc and DMD. The highest frequencies of deletion were detected for Caspase8 and MTAP. Gained genes, classified by hierarchical clustering, were mainly on 17q21-tel; 20q; 11q13; 3q27-29 and the X chromosome. Among these, gains of EGFR at 7p, FGF4/FGF3, CCND1 and EMS1 at 11q13, and AIB1 at 20q were significantly associated with lymph node metastasis. The genomic profiles of FHIT and EXT1 in AQ-associated and non-AQ-associated OSCCs exhibited the most prominent differences. RT-PCR confirmed the significant increase of TP63 and Serpine1 mRNA expression in OSCC relative to non-malignant matched tissue. A significant increase in Serpine1 immunoreactivity was observed from non-malignant matched tissue to OSCC. However, there was no correlation between the frequent genomic loss of Caspase 8 and a significant decrease in Caspase8 expression. These data demonstrate that genomic profiling can be useful in analysing pathogenetic events involved in the genesis or progression of OSCC. Show less

In the budding yeast Saccharomyces cerevisiae, progress of the cell cycle beyond the major control point in G1 phase, termed START, requires activation of the evolutionarily conserved Cdc28 protein kinase by direct association with G1 cyclins. We have used a conditional lethal mutation in CDC28 of S. cerevisiae to clone a functional homologue from the human fungal pathogen Candida albicans. The protein sequence, deduced from the nucleotide sequence, is 79% identical to that of S. cerevisiae Cdc28 and as such is the most closely related protein yet identified. We have also isolated from C. albicans two genes encoding putative G1 cyclins, by their ability to rescue a conditional G1 cyclin defect in S. cerevisiae; one of these genes encodes a protein of 697 amino acids and is identical to the product of the previously described CCN1 gene. The second gene codes for a protein of 465 residues, which has significant homology to S. cerevisiae Cln3. These data suggest that the events and regulatory mechanisms operating at START are highly conserved between these two organisms. Show less