Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanisms that target both the innate and adaptive immune responses. However, how HCMV encoded proteins are involved in this immune escape is not clear. Here, we show that HCMV glycoprotein US9 inhibits the IFN-β response by targeting the mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways. US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leading to promotion of MAVS leakage from the mitochondria. Furthermore, US9 disrupts STING oligomerization and STING–TBK1 association through competitive interaction. Intriguingly, US9 blocks interferon regulatory factor 3 (IRF3) nuclear translocation and its cytoplasmic domain is essential for inhibiting IRF3 activation. Mutant HCMV lacking US7-16 is impaired in antagonism of MAVS/STING-mediated IFN-β expression, an effect that is reversible by the introduction of US9. Our findings indicate that HCMV US9 is an antagonist of IFN signaling to persistently evade host innate antiviral responses.

Although elevated syndecan-2 expression is known to be crucial for the tumorigenic activity in colon carcinoma cells, how syndecan-2 regulates colon cancer is unclear. In human colon adenocarcinoma tissue samples, we found that both mRNA and protein expression of syndecan-2 were increased, compared with the neighboring normal epithelium, suggesting that syndecan-2 plays functional roles in human colon cancer cells. Consistent with this notion, syndecan-2-overexpressing HT-29 colon adenocarcinoma cells showed enhanced migration/invasion, anchorage-independent growth, and primary tumor formation in nude mice, paralleling their morphological changes into highly tumorigenic cells. In addition, our experiments revealed that syndecan-2 enhanced both expression and secretion of matrix metalloproteinase-7 (MMP-7), directly interacted with pro-MMP-7, and potentiated the enzymatic activity of pro-MMP-7 by activating its processing into the active MMP-7. Collectively, these data strongly suggest that syndecan-2 functions as a docking receptor for pro-MMP-7 in colon cancer cells.The characteristics and functions of cancer cells are critically influenced by the actions of cell adhesion receptors, which mediate interactions of cancer cells with the extracellular matrix (ECM) 3 and the cytoskeleton (1). At different points during carcinogenesis, the cell adhesion receptors regulate various cancer cell functions, including cell growth, differentiation, cell survival, angiogenesis, and inflammation (2, 3). Thus, the cancer-specific characteristics and functions of cancer cells are due to the expression and utilization of a distinct set of adhesion receptors that show different expression patterns in normal cells. One group of cancer-related cell adhesion receptors are the syndecans, which are cell surface heparan sulfate proteoglycans known to play diverse roles in cell adhesion and cell communication by serving as co-receptors for both cell signaling and ECM molecules (4). At the plasma membrane, syndecans are capable of transmitting signals from the extracellular environment to the intracellular compartment, thereby regulating adhesion-dependent signal transduction during cell growth (5, 6), cell adhesion and migration (6, 7), cytoskeleton organization (7, 8), and cell differentiation (9). Numerous studies have examined the function of syndecans in various human tumors. Syndecan-1 expression is down-regulated in a great number of squamous cell carcinomas, including uterine cervix, lung, and colorectal cancer (2, 10 -12). However, in other studies, syndecan-1 expression is reportedly up-regulated in prostate, lung, and breast cancers (13-15). In the case of syndecan-2, it has been reported that, in normal tissues, syndecan-2 is expressed in mesenchymal cells but not in normal epithelial cells. However, we found that syndecan-2 expression is increased in several epithelial-driven colon carcinoma cells, and this up-regulation is necessary for the tumorigenic activity of colon carcinoma cells (16). Therefore, it is likely that a...

ObjectivesThe objective of this paper is to describe the Health Insurance Review and Assessment Service (HIRA)'s payment request (PARE) system that plays the role of the gateway for all health insurance claims submitted to HIRA, and the claim review support (CRS) system that supports the work of claim review experts in South Korea.MethodsThis study describes the two systems' information technology (IT) infrastructures, their roles, and quantitative analysis of their work performance. It also reports the impact of these systems on claims processing by analyzing the health insurance claim data submitted to HIRA from April 1 to June 30, 2011.ResultsThe PARE system returned to healthcare providers 2.7% of all inpatient claims (97,930) and 0.1% of all outpatient claims (317,007) as un-reviewable claims. The return rate was the highest for the hospital group as 0.49% and the lowest rate was found in clinic group. The CRS system's detection rate of the claims with multiple errors in inpatient and outpatient areas was 23.1% and 2.9%, respectively. The highest rate of error detection occurred at guideline check-up stages in both inpatient and outpatient groups.ConclusionsThe study found that HIRA's two IT systems had a critical role in reducing heavy administrative workloads through automatic data processing. Although the return rate of the problematic claims to providers and the error detection rate by two systems was low, the actual count of the returned claims was large. The role of IT will become increasingly important in reducing the workload of health insurance claims review.

Objective A new age of neuromodulation is emerging: one of restorative neuroengineering and neuroprosthetics. As novel device systems move toward regulatory evaluation and clinical trials, a critical need arises for evidence‐based identification of potential sources of hardware‐related complications to assist in clinical trial design and mitigation of potential risk. Materials and Methods The objective of this systematic review is to provide a detailed safety analysis for future intracranial, fully implanted, modular neuroprosthetic systems. To achieve this aim, we conducted an evidence‐based analysis of hardware complications for the most established clinical intracranial modular system, deep brain stimulation (DBS), as well as the most widely used intracranial human experimental system, the silicon‐based (Utah) array. Results Of 2328 publications identified, 240 articles met the inclusion criteria and were reviewed for DBS hardware complications. The most reported adverse events were infection (4.57%), internal pulse generator malfunction (3.25%), hemorrhage (2.86%), lead migration (2.58%), lead fracture (2.56%), skin erosion (2.22%), and extension cable malfunction (1.63%). Of 433 publications identified, 76 articles met the inclusion criteria and were reviewed for Utah array complications. Of 48 human subjects implanted with the Utah array, 18 have chronic implants. Few specific complications are described in the literature; hence, implant duration served as a lower bound for complication‐free operation. The longest reported duration of a person with a Utah array implant is 1975 days (~5.4 years). Conclusions Through systematic review of the clinical and human‐trial literature, our study provides the most comprehensive safety review to date of DBS hardware and human neuroprosthetic research using the Utah array. The evidence‐based analysis serves as an important reference for investigators seeking to identify hardware‐related safety data, a necessity to meet regulatory requirements and to design clinical trials for future intracranial, fully implanted, modular neuroprosthetic systems.

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