METADHERIN FUNCTIONS AS A LAMININ RECEPTOR THAT IS ESSENTIAL FOR METASTASIS AND IS ASSOCIATED WITH POOR SURVIVAL IN OSTEOSARCOMA

Osteosarcoma is a highly invasive bone malignancy in which metastasis accounts for the vast majority of death and morbidity in patients. Understanding the mechanisms controlling metastasis is essential for improving patient survival in this disease. In order to improve the clinical outcomes for patients with poor prognosis, it is urgent to find new therapeutic targets to block metastasis in this disease. Recent studies have shown that Metadherin (MTDH) plays an essential role in mediating tumorigenesis and metastasis in a variety of human cancers. Our study assessed the role of MTDH in osteosarcoma metastasis and elucidated the mechanisms underlying its metastasis-promoting activity. To evaluate the expression of MTDH in primary and metastatic lesions of osteosarcoma, two tissue microarrays containing patient-derived primary and metastatic tumor specimens were examined by immunohistochemical staining with anti-MTDH antibody. We also examined MTDH in a cDNA array expression database made from pretreatment diagnostic biopsies of high-grade osteosarcoma patients to further assess the correlation between MTDH expression and clinical outcome. We used western blot, qPCR, and flow cytometry to measure the expression of MTDH in a panel of osteosarcoma cell lines. In parallel experiments we used MTDH-specific shRNA to reduce endogenous MTDH expression, and blocked cell surface MTDH by anti-MTDH antibodies. The impact of MTDH inhibition was assessed in vitro using transwell migration assays and matrigel invasion assays. In addition, we developed an orthotopic xenograft mouse model to study the relationship between MTDH expression and osteosarcoma pulmonary metastasis. To investigate the role of MTDH in cell-extracellular matrix (ECM) interaction and to identify the extracellular binding partner for cell surface MTDH, a series of adhesion assays were performed, followed by bidirectional co-immunoprecipitation. We have demonstrated that MTDH is up-regulated in human osteosarcoma cell lines and patient-derived specimens compared with normal human osteoblasts. Overexpression of MTDH is more profound in metastatic lesions compared to primary tumors and is correlated with poor clinical outcomes in osteosarcoma patients. MTDH knockdown and blockade of cell surface MTDH significantly reduced migration and invasion in osteosarcoma cells. In the in vivo experiments, down-regulation of MTDH in osteosarcoma cells delayed primary tumor growth and prohibited pulmonary metastasis. Both in vitro and in vivo studies confirmed the critical role of MTDH in the invasive and metastatic capacity of osteosarcoma cells. More importantly, we have identified the significance of cell surface localization of MTDH in mediating osteosarcoma motility and invasiveness. We showed that MTDH exists as a type II membrane protein in osteosarcoma cells and its expression on cell surface is facilitating cell invasion by means of modulating cell adhesion to the ECM through interaction with Laminin. In total, these observations establish MTDH as a promising target for therapeutic interventions in metastatic osteosarcoma. The novel connection between MTDH and extracellular laminin also establishes a new paradigm for the function of MTDH in mediating tumor cell metastasis

Exploring the Significance of Digital Skills Training for Accountants

Accounting firm leaders face a challenge with employees who lack digital skills. Employees without relevant digital skills put the accounting firm at a competitive disadvantage. Grounded in human capital theory, the purpose of this qualitative multiple case study was to explore strategies regional accounting firm leaders used to help employees improve digital skills. Data were collected from six semistructured interviews with partners, directors, and managers with three years or more of experience who participated in the training and professional development process at four regional accounting firms in the Houston, Texas area. The review of company documents and company website postings triangulated the semistructured interviews. Data analysis entailed coding, conceptualizing concepts, identifying themes, and member checking. Three themes emerged, including digital skills needed for success, demonstrating investment in digital skills training, and benefits and challenges of digital skills training. One key recommendation was to offer training opportunities and intergenerational mentorship to accounting employees. The implications for positive social change include the potential to increased employee employability, work and life balance, job satisfaction, and client satisfaction, which may improve local communities\u27 economic stability and growth

High-bandwidth nanopositioning via active control of system resonance

Acknowledgements This work was supported in part by the National Natural Science Foundation of China (Grant Nos. U2013211 and 51975375), the Open Foundation of the State Key Laboratory of Fluid Power and Mechatronic Systems, China (Grant No. GZKF-202003), and the Binks Trust Visiting Research Fellowship (2018), University of Aberdeen, UK, awarded to Dr. Sumeet S. Aphale.Peer reviewedPublisher PD

Fractional Repetitive Control of Nanopositioning Stages for High-Speed Scanning Using Low-Pass FIR Variable Fractional Delay Filter

This work was supported by the National Natural Science Foundation of China under Grant 51975375, the Binks Trust Visiting Research Fellowship (2018) (University of Aberdeen, UK) awarded to Dr. Sumeet S. Aphale and the SJTU overseas study grant awarded to Linlin Li. The authors would like to thank Mr. Wulin Yan for his assistance with the experiments.Peer reviewedPostprin

l-Peptide functionalized dual-responsive nanoparticles for controlled paclitaxel release and enhanced apoptosis in breast cancer cells

Nanoparticles and macromolecular carriers have been widely used to increase the efficacy of chemotherapeutics, largely through passive accumulation provided by their enhanced permeability and retention effect. However, the therapeutic efficacy of nanoscale anticancer drug delivery systems is severely truncated by their low tumor-targetability and inefficient drug release at the target site. Here, the design and development of novel l-peptide functionalized dual-responsive nanoparticles (l-CS-g-PNIPAM-PTX) for active targeting and effective treatment of GRP78-overexpressing human breast cancer in vitro and in vivo are reported. l-CS-g-PNIPAM-PTX NPs have a relative high drug loading (13.5%) and excellent encapsulation efficiency (74.3%) and an average diameter of 275 nm. The release of PTX is slow at pH 7.4 and 25 °C but greatly accelerated at pH 5.0 and 37 °C. MTT assays and confocal experiments showed that the l-CS-g-PNIPAM-PTX NPs possessed high targetability and antitumor activity toward GRP78 overexpressing MDA-MB-231 human breast cancer cells. As expected, l-CS-g-PNIPAM-PTX NPs could effectively treat mice bearing MDA-MB-231 human breast tumor xenografts with little side effects, resulting in complete inhibition of tumor growth and a high survival rate over an experimental period of 60 days. These results indicate that l-peptide-functionalized acid - and thermally activated - PTX prodrug NPs have a great potential for targeted chemotherapy in breast cancer.</p

Accruals, Earnings Quality and Research Methodology

We first review prior earnings management studies with an emphasis on discretionary accruals as a proxy for earnings management. Discretionary accruals are estimated using widely accepted models, such as the Jones model or its updated ones with additional control variables to improve their prediction power. Nonetheless, estimated discretionary accruals are still subject to model specification errors. Then, we review alternative methods to identify earnings management by evaluating earnings distribution properties and frequencies of digits in collected accounting numbers. These alternative methods can identify anomalies in earnings distributions or frequencies of digits but cannot explain how such anomalies take place. Accordingly, future studies of earnings management may employ these alternative methods in conjunction with discretionary accruals to offer a better insight into earnings management practices

Are Onconeural Antibodies a Clinical Phenomenology in Paraneoplastic Limbic Encephalitis?

Paraneoplastic neurological syndromes (PNSs) occur in patients with cancer and can cause clinical symptoms and signs of dysfunction of the nervous system that are not due to a local effect of the tumor or its metastases. Most of these clinical syndromes in adults are associated with lung cancer, especially small cell lung cancer (SCLC), lymphoma, and gynecological tumors. The finding of highly specific antibodies directed against onconeural antigens has revolutionized the diagnosis and promoted the understanding of these syndromes and led to the current hypothesis of an autoimmune pathophysiology. Accumulating data strongly suggested direct pathogenicity of these antibodies. The field of PNS has expanded rapidly in the past few years with the discovery of limbic encephalitis associated with glutamic acid decarboxylase (GAD) 65, the voltage (VGKC-gated potassium channel) complex, the methyl (N-NMDA-D-aspartate), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and gamma aminobutyric acid (GABA) (B) receptors, and so forth. Despite this, the clinical spectrum of these diseases has not yet been fully investigated. The clinical importance of these conditions lies in their frequent response to immunotherapies and, less commonly, their association with distinctive tumors. This review provides an overview on the pathogenesis and diagnosis of PNS, with emphasis on the role of antibodies in limbic encephalitis