Biosensors, combining a selective biological recognition element and a sensitive transducer, are versatile analytical tools applied more and more in different fields, such as medicine, food quality ...and safety control, and environment pollution monitoring. They are expected to play an increasingly important role in the improvement of life quality. In this context, the present work covers recent approaches in design and development of biosensors applied for analysis of real samples of medical, environmental or industrial relevance. The described sensors meet the sensitivity, selectivity, and response time required by their applications. Moreover, they are designed to avoid contamination of the monitored systems with undesirable components and to minimise the damage of living organisms (when it comes to in vivo monitoring).
Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno‐oncology (IO) the aim is to direct the ...patient’s own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD‐L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug‐development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds’ pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.
Extreme ozone minima represent localized and temporally brief (several days) reductions in column ozone amounts below some chosen absolute level. Although such minima at middle to high northern ...latitudes are known to be primarily dynamical in origin, a remaining issue is whether heterogeneous chemical loss processes may also contribute significantly to their formation. A case in point is the record low 165 Dobson units (DU) minimum occurring on November 30, 1999, when temperatures near 30 hPa at the location of the minimum were lower than the threshold for the formation of type I polar stratospheric clouds (PSC). An examination of Polar Ozone and Aerosol Measurement III data for times surrounding the event shows that PSCs were indeed present in the vicinity where the ozone minimum was observed. However, archived data show that a similar extreme minimum of 167 DU with characteristics comparable to those of the November 30, 1999, minimum occurred on October 30, 1985, when no PSCs were present. An ensemble of 71 extreme ozone minima with amplitudes under 215 DU exhibit a nearly linear relationship between ozone minimum deviations from the zonal mean and corresponding 30‐hPa temperature deviations. Such a relationship is predicted by analytic transport models which assume that vertical motions (i.e., upwelling) are responsible for the ozone minima. Temperature deviations near 30‐hPa were unusually large for both the November 30, 1999, and the October 30, 1985, events, implying unusually rapid upward transport for these events. All 71 minima occur in regions where deviations from the zonal mean of 330 K potential vorticity are negative, implying an additional contribution to their formation by quasi‐horizontal transport. The timescale for column ozone reductions during extreme ozone minima events is also determined and found to be at least 20 times more rapid than expected from known chemical loss processes. The data are therefore most consistent with a purely dynamical origin for extreme ozone minima in general and the November 30, 1999, event in particular. As was shown by earlier work, the basic dynamical process involves a combination of isentropic transport of ozone‐poor air from the tropical upper troposphere and rapid upwelling over upper tropospheric anticyclonic disturbances resulting from poleward Rossby wave breaking events.
Some methods to look for exact solutions of nonlinear differential equations are discussed. It is shown that many popular methods are equivalent to each other. Several recent publications with “new” ...solitary wave solutions for the Kuramoto-Sivashinsky equation are analyzed. We demonstrate that all these solutions coincide with the known ones.
The osma(II)cycles Os(phpy)(LL)2PF6 (LL = 1,10-phen (3a) and 4,4‘-Me2-2,2‘-bpy (3b)) are made from (η6-C6H6)Os(μ-Cl)Cl2 (1) either via transmetalation using the Hg(phpy)2 organomercurial in MeOH or ...via the sp2-C−H bond cleavage of 2-phenylpyridine (phpyH) in MeCN to afford (η6-C6H6)Os(phpy)Cl or (η6-C6H6)Os(phpy)(MeCN)PF6, respectively. The latter two react cleanly with LL to give 3a and 3b, the MII/III redox potentials of which equal 30 and −100 mV (vs Ag/AgCl), respectively. The electrochemically made OsIII species oxidize rapidly reduced glucose oxidase. The second-order rate constant equals 1.1 × 107 M-1 s-1 for 3a at 25 °C, pH 7.
Abstract
MEDI9197 (formerly 3M-052) is a sustained-release imidazoquinoline toll like receptor (TLR) TLR7/8 agonist designed with a lipid tail that, when injected, is retained within the tumor. This ...has been shown in pharmacokinetic studies in mice and rats injected with MEDI9197 via the subcutaneous (SC) or intratumoral (IT, mouse only) routes. Stimulation of TLR7 and TLR8 in primary human dendritic cells induces the release of interferon-alpha (IFN-a) from plasmacytoid dendritic cells (pDCs) and interleukin 12 (IL-12) from myeloid dendritic cells (mDCs). Intratumoral administration of MEDI9197 induces a local immune response characterized by upregulation of genes involved in activation of innate and adaptive immunity both from the injected tumor and tumor draining lymph node. Furthermore, flow cytometric analysis of tumor infiltrating lymphocytes (TILs) show increased expression of activation markers, such as CD69, on natural killer (NK) cells and CD8 cytotoxic T cells. This local stimulation of immune cells with MEDI9197 results in tumor growth inhibition as shown in the B16F10 luc syngeneic mouse tumor model using in vivo imaging system (IVIS) equipment. Additionally, combination of MEDI9197 with immune checkpoint inhibitors enhances the efficacy observed in syngeneic mouse tumor models. The data presented shows intratumoral administration of MEDI9197 induces local immune activation leading to tumor growth inhibition in preclinical models of cancer. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials.
Citation Format: Stefanie Mullins, Iwen Grigsby, Lester I. Harrison, Song Ren, Serguei Soukharev, Lesley Young, James M. Elvecrog, Robert W. Wilkinson, Mark A. Tomai, Ronald Herbst, John P. Vasilakos, Andrew J. Leishman. Local immune activation resulting in tumor growth inhibition with MEDI9197 - an intratumorally administered TLR7/8 agonist. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1475.
MEDI9197 (formerly 3M-052) is a sustained-release imidazoquinoline toll like receptor (TLR) TLR78 agonist designed with a lipid tail that, when injected, is retained within the tumor. This has been ...shown in pharmacokinetic studies in mice and rats injected with MEDI9197 via the subcutaneous (SC) or intratumoral (IT, mouse only) routes. Stimulation of TLR7 and TLR8 in primary human dendritic cells induces the release of interferon-alpha (IFN-a) from plasmacytoid dendritic cells (pDCs) and interleukin 12 (IL-12) from myeloid dendritic cells (mDCs). Intratumoral administration of MEDI9197 induces a local immune response characterized by upregulation of genes involved in activation of innate and adaptive immunity both from the injected tumor and tumor draining lymph node. Furthermore, flow cytometric analysis of tumor infiltrating lymphocytes (TILs) show increased expression of activation markers, such as CD69, on natural killer (NK) cells and CD8 cytotoxic T cells. This local stimulation of immune cells with MEDI9197 results in tumor growth inhibition as shown in the B16F10 luc syngeneic mouse tumor model using in vivo imaging system (IVIS) equipment. Additionally, combination of MEDI9197 with immune checkpoint inhibitors enhances the efficacy observed in syngeneic mouse tumor models. The data presented shows intratumoral administration of MEDI9197 induces local immune activation leading to tumor growth inhibition in preclinical models of cancer. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials.
ABSTRACT
Deficiency in a coagulation factor VIII (FVIII) causes a genetic disorder hemophilia A, which is treated by repeated infusions of expensive FVIII products. Recombinant FVIII (rFVIII), the ...culmination of years of extensive international research, is an important alternative to plasma-derived FVIII (pdFVIII) and is considered to have a higher margin of safety. Advances in biotechnology allowed production of rFVIII at industrial scale, which significantly improved treatment of hemophilia A patients. We review the contemporary methods used for FVIII expression in mammalian cell culture systems and discuss the factors responsible for insufficient recoveries of rFVIII, such as inefficient accumulation of FVIII mRNA in the cell, complexity of the mechanisms of FVIII secretion, and instability of secreted FVIII. The approaches to improve the yield of rFVIII in cell culture systems include genetic engineering of B-domain-deleted FVIII, introduction of introns into FVIII cDNA constructs for more efficient processing and accumulation of FVIII mRNA, and introduction of mutations into chaperone-binding sites of FVIII to improve its secretion. Design of FVIII with prolonged half-life in vivo is considered as another promising direction in improving rFVIII protein and efficiency of hemophilia A therapy. As an alternative to expression of rFVIII in cell culture systems, we discuss production of rFVIII in transgenic animals, where high levels of rFVIII have been successfully secreted into milk. We also pay attention to the major limitations of this approach, such as safety issues associated with potential transmission of animal pathogens. Finally, we present a brief characterization of commercial recombinant FVIII products currently available on the market for hemophilia A treatment.
Status of the KEDR detector Anashin, V.V; Aulchenko, V.M; Baibusinov, B.O ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2002, Letnik:
478, Številka:
1
Journal Article
Recenzirano
KEDR is a general-purpose detector for experiments at the VEPP-4M e
+e
−-collider in the energy range 2
E=2.0–
12
GeV
. All detector subsystems (except the aerogel Cherenkov counters) have been ...installed into the detector at VEPP-4M. Some preliminary data have been taken in the energy region of the J/Ψ meson. The tuning of the detector and the VEPP-4M collider is in progress. Preliminary results on the detector performance are presented. The future experimental program for the KEDR detector is discussed.
The first and second Painlevé equation hierarchies are considered. The relations between them are given. The Bäcklund transformations for the second Painlevé equations of higher order are presented. ...Some rational solutions of these equations are obtained. The indices for the first and second Painlevé equations of fourth order are found. These equations are shown to pass the Painlevé test. Lax pairs for the first and second Painlevé equations of higher order are given. The transcendence of the solutions for the first Painlevé hierarchy is discussed.
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