Clinical Features of Ehlers-Danlos Syndrome

Background/PurposeEhlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous connective tissue disorder characterized by hyperextensibility of the skin, hypermobility of joints, and tissue fragility. This retrospective study analyzed the characteristics of patients with EDS.MethodsReview of medical records identified 16 cases of EDS during the study period from November 1997 to October 2002. Data on these patients, including clinical presentation, physical examinations, Beighton score, echocardiogram, bone mineral density findings and clinical classification, were analyzed.ResultsThe age of the patients ranged from 13 months to 36 years. All patients had skin hyperextensibility, joint hypermobility (Beighton score > 5 points), and tissue fragility. Complete bone mineral density study was performed in 11 patients and revealed that all had osteoporosis. Echocardiographic study was performed in 14 patients and showed aortic root dilatation/valve prolapse in 6/14 (43%). Other common features of EDS had the following prevalence: premature rupture of membranes in 3/16 (19%); prematurity in 3/16 (19%); neonatal hypotonia in 5/16 (31%); congenital hip dislocation in 3/16 (19%); unstable gait in 7/16 (44%); bone fracture(s) in 3/16 (19%); motor delay in 3/16 (19%); scoliosis in 3/16 (19%); short stature in 7/16 (44%); and positive family history in 8/16 (50%). All patients had a Beighton score of more than 5 points.ConclusionThe results of this study emphasize the importance of echocardiographic monitoring of aortic size and valvular condition, and assessment of bone mineral density in patients with EDS. Clinical evaluation and counseling should be undertaken prior to pregnancy in patients with EDS because of the risk from labor and vaginal delivery in patients with type IV and the inability to distinguish EDS subtypes in Taiwan due to the unavailability of biochemical assay or molecular mutation analysis as part of standard care

ATACgraph: Profiling genome-wide chromatin accessibility from ATAC-seq

Assay for transposase-accessible chromatin using sequencing data (ATAC-seq) is an efficient and precise method for revealing chromatin accessibility across the genome. Most of the current ATAC-seq tools follow chromatin immunoprecipitation sequencing (ChIP-seq) strategies that do not consider ATAC-seq-specific properties. To incorporate specific ATAC-seq quality control and the underlying biology of chromatin accessibility, we developed a bioinformatics software named ATACgraph for analyzing and visualizing ATAC-seq data. ATACgraph profiles accessible chromatin regions and provides ATAC-seq-specific information including definitions of nucleosome-free regions (NFRs) and nucleosome-occupied regions. ATACgraph also allows identification of differentially accessible regions between two ATAC-seq datasets. ATACgraph incorporates the docker image with the Galaxy platform to provide an intuitive user experience via the graphical interface. Without tedious installation processes on a local machine or cloud, users can analyze data through activated websites using pre-designed workflows or customized pipelines composed of ATACgraph modules. Overall, ATACgraph is an effective tool designed for ATAC-seq for biologists with minimal bioinformatics knowledge to analyze chromatin accessibility. ATACgraph can be run on any ATAC-seq data with no limit to specific genomes. As validation, we demonstrated ATACgraph on human genome to showcase its functions for ATAC-seq interpretation. This software is publicly accessible and can be downloaded at https://github.com/RitataLU/ATACgraph

TRIM28-Regulated Transposon Repression Is Required for Human Germline Competency and Not Primed or Naive Human Pluripotency.

Transition from primed to naive pluripotency is associated with dynamic changes in transposable element (TE) expression and demethylation of imprinting control regions (ICRs). In mouse, ICR methylation and TE expression are each regulated by TRIM28; however, the role of TRIM28 in humans is less clear. Here, we show that a null mutation in TRIM28 causes significant alterations in TE expression in both the naive and primed states of human pluripotency, and phenotypically this has limited effects on self-renewal, instead causing a loss of germline competency. Furthermore, we discovered that TRIM28 regulates paternal ICR methylation and chromatin accessibility in the primed state, with no effects on maternal ICRs. Taken together, our study shows that abnormal TE expression is tolerated by self-renewing human pluripotent cells, whereas germline competency is not

A rare complication in a child undergoing chemotherapy for acute lymphoblastic leukemia: Superior sagittal sinus thrombosis

AbstractWe report the case of a 4-year-old boy with acute lymphoblastic leukemia in high-risk group who suffered from generalized tonic-colonic seizure evolving into status epilepticus, and subsequent left hemiparesis during his first reinduction chemotherapy, consisting of dexamethasone, vincristine, l-asparaginase, and epirubicin. Superior sagittal sinus and cerebral venous thrombosis, predominantly in right side, were proved by brain magnetic resonance imaging. After aggressive treatment with low-molecular weight heparin (LMWH), left hemiparesis improved in 1 week. And he was fully ambulatory 3 weeks later. The second cycle of reinduction chemotherapy was conducted smoothly with the concomitant use of LMWH. This case illustrates the strong correlation of the rare thrombotic complication, superior sagittal sinus thrombosis, and hypercoagulable status secondary to combination use of l-asparaginase and corticosteroid. Early and vigilant recognition of superior sagittal sinus thrombosis and prompt anticoagulation with LMWH may prevent further neurological damage

MethylC-analyzer: A comprehensive downstream pipeline for the analysis of genome-wide DNA methylation

DNA methylation is a crucial epigenetic modification involved in multiple biological processes and diseases. Current approaches for measuring genome-wide DNA methylation via bisulfite sequencing (BS-seq) include whole-genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS), and enzymatic methyl-seq (EM-seq). The computational analysis tools available for BS-seq data include customized aligners for mapping bisulfite-converted reads and computational pipelines for downstream data analysis. Current post-alignment methylation tools are specialized for the interpretation of CG methylation, which is known to dominate mammalian genomes, however, non-CG methylation (CHG and CHH, where H refers to A, C, or T) is commonly observed in plants and fungi and is closely associated with gene regulation, transposon silencing, and plant development. Thus, we have developed a MethylC-analyzer to analyze and visualize post-alignment WGBS, RRBS, and EM-seq data focusing on CG. The tool is able to also analyze non-CG sites to enhance deciphering genomes of plants and fungi. By processing aligned data and gene location files, MethylC-analyzer generates a genome-wide view of methylation levels and methylation in user-specified genomic regions. The meta-plot, for example, allows the investigation of DNA methylation within specific genomic elements. Moreover, our tool identifies differentially methylated regions (DMRs) and investigates the enrichment of genomic features associated with variable methylation. MethylC-analyzer functionality is not limited to specific genomes, and we demonstrated its performance on both plant and human BS-seq data. MethylC-analyzer is a Python- and R-based program designed to perform comprehensive downstream analyses of methylation data, providing an intuitive analysis platform for scientists unfamiliar with DNA methylation analysis. It is available as either a standalone version for command-line uses or a graphical user interface (GUI) and is publicly accessible at https://github.com/RitataLU/MethylC-analyzer

Visfatin mediates malignant behaviors through adipose-derived stem cells intermediary in breast cancer

Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression

Reciprocal regulation of MicroRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells

BACKGROUND: MicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%. METHODS: The expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors. RESULTS: We observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3′UTR of IGF1R mRNA into the 3′UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3′UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling. CONCLUSION: Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation