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[en] The batch assay has been conventionally used for radioimmunoassay (RIA) because of its technical robustness and practical convenience. However, it has limitations in terms of the relative lag of report time due to the necessity of multiple assays in a small number of samples compared with the random assay technique. In this study, we aimed to verify whether the random assay technique can be applied in RIA and is feasible in daily practice. The coefficients of variation (CVs) of eight standard curves within a single kit were calculated in a CA-125 immunoradiometric assay (IRMA) for the reference of the practically ideal CV of the CA-125 kit. Ten standard curves of 10 kits from 2 prospectively collected lots (pLot) and 85 standard curves of 85 kits from 3 retrospectively collected lots (Lot) were obtained. Additionally, the raw measurement data of both 170 control references and 1123 patients' sera were collected retrospectively between December 2015 and January 2016. A standard curve of the first kit of each lot was used as a master standard curve for a random assay. The CVs of inter-kits were analyzed in each lot, respectively. All raw measurements were normalized by decay and radioactivity. The CA-125 values from control samples and patients' sera were compared using the original batch assay and random assay. In standard curve analysis, the CVs of inter-kits in pLots and Lots were comparable to those within a single kit. The CVs from the random assay with normalization were similar to those from the batch assay in the control samples (CVs % of low/high concentration; Lot1 2.71/1.91, Lot2 2.35/1.83, Lot3 2.83/2.08 vs. Lot1 2.05/1.21, Lot2 1.66/1.48, Lot3 2.41/2.14). The ICCs between the batch assay and random assay using patients' sera were satisfactory (Lot1 1.00, Lot2 0.999, Lot3 1.00). The random assay technique could be successfully applied to the conventional CA-125 IRMA kits. The random assay showed strong agreement with the batch assay. The random assay procedure could increase the flexibility and decrease the turnaround time of the radioimmunoassay technique
[en] Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment
[en] The Physics and Advanced Technologies (PAT) Directorate was created in July 2000 by Bruce Tarter, Director of Lawrence Livermore National Laboratory (LLNL). The Director called for the new organization to execute and support programs that apply cutting-edge physics and advanced technology to develop integrated solutions to problems in national security, fusion energy, information science, health care, and other national grand challenges. When I was appointed a year later as the PAT Directorate's first Associate Director, I initiated a strategic planning project to develop a vision, mission, and long-term goals for the Directorate. We adopted the goal of becoming a leader in frontier physics and technology for twenty-first-century national security missions: Stockpile Stewardship, homeland security, energy independence, and the exploration of space. Our mission is to: (1) Help ensure the scientific excellence and vitality of the major LLNL programs through its leadership role in performing basic and applied multidisciplinary research and development with programmatic impact, and by recruiting and retaining science and technology leaders; (2) Create future opportunities and directions for LLNL and its major programs by growing new program areas and cutting-edge capabilities that are synergistic with, and supportive of, its national security mission; (3) Provide a direct conduit to the academic and high-tech industrial sectors for LLNL and its national security programs, through which the Laboratory gains access to frontier science and technology, and can impact the science and technology communities; (4) Leverage unique Laboratory capabilities, to advance the state universe. This inaugural PAT Annual Report begins a series that will chronicle our progress towards fulfilling this mission. I believe the report demonstrates that the PAT Directorate has a strong base of capabilities and accomplishments on which to build in meeting its goals. Some of the highlights include: (1) Leadership of the Laboratory's Physical Data Research Program that provides fundamental physics information for the Stockpile Stewardship Program. (2) Development of the handheld Microbead Immunoassay Dipstick System that will allow relatively untrained first-responders to run sophisticated onsite diagnostics for pathogens, including those associated with biowarfare agents, by using a simple, one-step measurement. (3) Major advances in target design for inertial fusion energy research using both laser and ion-beam drivers. (4) Development of the Advanced Technology Kill Vehicle concept for use as a high-performance interceptor in a broad range of missile defense programs. Over the course of the past decade, the Laboratory has seen its major program evolve from weapons research, development, and testing, to Stockpile Stewardship. Today, the country's national security priorities are changing rapidly: nuclear security is becoming a broader set of missions, and the Laboratory is being asked to contribute to a range of new mission areas from countering bioterrorism to ensuring information security. As we embark on the twenty-first century, the new PAT Directorate is poised to help lead the Laboratory's response to the country's changing national security needs
[en] Molecular analyses of the c-kit and PDGFRα genes have contributed greatly to our understanding of the development of gastrointestinal stromal tumors (GISTs), but little is known about their malignant potential. The aim of our study was to evaluate cell cycle regulators as potential prognostic markers in GISTs. We investigated 104 KIT positive GISTs from various tumor sites in immunoassays on CD34, Ki67 and particularly on P53, BCL-2 and Cyclin D1. The results were compared with tumor size, mitotic rate, proliferative activity, histological subtype, nuclear atypia and risk assessment according to Fletcher and Miettinen. Occurrence of metastases and survival were also taken into account. The expression of P53 was significantly correlated with high risk criteria towards malignancy and epithelioid differentiation in GISTs. Likewise P53 label correlated significantly with the established prognostic indicators: tumor size, mitotic rate, nuclear atypia and proliferative activity. Regarding the site of tumor presentation, P53 was not a decisive factor. BCL-2 and Cyclin D1 expression was not related to any of the prognostic indicators. The present data identified P53 being a recommendable marker for predicting the risk of malignancy in GISTs. In addition, we found P53 significantly correlated with epithelioid tumor differentiation, independent of tumor site. BCL-2 and Cyclin D1, however, did not prove to be deciding markers for diagnosis and prognosis
[en] A powerful route to utilizing magnetic nanoparticles as labels in magnetic immunoassays is to exploit their non-linear response when they are exposed to a multi-frequency alternating magnetic field. We have upgraded this non-linear method allowing for the detection, discrimination and quantification of particles of two kinds when mixed together, with no need for spatial resolution. Each kind of particle is characterized by a specific magnetic signature based on d2B(H)/dH2. Appropriate data processing of the signature measured on a mixture of both particles allows for obtaining the amount of each particle. This will enable utilizing magnetic labels for multiparametric magnetic immunoassays.
[en] A new type of biosensor has been developed based on detection of nanosized superparamagnetic particles that serve as labels in bioreactions. The method is based on non-linear magnetic material detection by a magnetic field having components at two frequencies f 1 and f 2. The response is measured at the combinatorial frequencies f i=mf 1+nf 2, where m and n are integers, e.g., f i=f 1±2f 2. Several highly sensitive readers of superparamagnetic particles have been designed and used for development of various formats of immunoassays, including those compatible with immunoconcentration and magnetic enrichment of antigens
[en] We study the amplification of the electromagnetic fluctuations, and the production of 'seeds' for the cosmic magnetic fields, in a class of string cosmology models whose scalar and tensor perturbations reproduce current observations and satisfy known phenomenological constraints. We find that the condition of efficient seeds production can be satisfied and compatible with all constraints only in a restricted region of parameter space, but we show that such a region has significant intersections with the portions of parameter space where the produced background of relic gravitational waves is strong enough to be detectable by aLIGO/Virgo and/or by eLISA.
[en] AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors