A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CADM1) is yet to be clearly identified. In this study, we first isolated MF-CADM1-specific fully human single-chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv-Fc antibodies (K103.1–4), multiple characterization studies, including antibody cross-species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI-H69, NCI-H146, and NCI-H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody-based targeting of MF-CADM1 may be an effective strategy to potentiate T cell-mediated SCLC death, and MF-CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy.     

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.     

Dual-wavelength cascaded Raman fibre laser

Dual-wavelength lasing at 1480 and 1500 nm has been demonstrated from a cascaded Raman fibre laser with a WDM coupler and two pairs of Bragg gratings. Intensity-adjustable, wavelength-tunable laser operation was achieved by tensile stress wavelength tuning of the gratings     

Mobile Small Cells for Further Enhanced 5G Heterogeneous Networks

A heterogeneous network (HetNet) is a network topology composed by deploying multiple HetNets under the coverage of macro cells (MCs). It can improve network throughput, extend cell coverage, and offload network traffic; for example, the network traffic of a 5G mobile communications network. A HetNet involves a mix of radio technologies and various cell types working together seamlessly. In a HetNet, coordination between MCs and small cells (SCs) has a positive impact on the performance of the networks contained within, and consequently on the overall user experience. Therefore, to improve user‐perceived service quality, HetNets require high‐efficiency network protocols and enhanced radio technologies. In this paper, we introduce a 5G HetNet comprised of MCs and both fixed and mobile SCs (mSCs). The featured mSCs can be mounted on a car, bus, or train and have different characteristics to fixed SCs (fSCs). In this paper, we address the technical challenges related to mSCs. In addition, we analyze the network performance under two HetNet scenarios — MCs and fSCs, and MCs and mSCs.     

基于媒体独立切换并提供QoS保证的跨UMTS和WiMAX无线异构网络的网络切换方案

The rapid growth and innovation of the various mobile communication technologies have caused a change in the paradigm of internet access. Wireless technologies such as WiMAX, WiFi and UMTS/LTE networks have shown great potential in dominating the wireless access markets. The existence of various access technologies requires a means for seamless internetworking to provide anywhere, anytime services without interruption in the ongoing session, especially in multimedia applications with rigid Quality of Services (QoS) requirements. The IEEE 802.21 Media Independent Handover (MIH) working group was formed to develop a set of mechanisms under a standard framework with the capability to support migration of mobile users across heterogeneous networks. Therefore, the implementation of handover is extremely important in the heterogeneous network environment. In order to guarantee various QoS requirements during handover execution especially in multimedia applications, in this paper we propose a novel MIH-based capacity estimation algorithm to execute handover with QoS provision supporting both horizontal and vertical handovers across UMTS and WiMAX networks. Simulation shows that the proposed mechanism achieves lower call dropping rate (highest approximate 3% ) and higher system throughput (average 92% ) than the basic handover method does.     

High-Efficiency Power Amplifier Using Novel Dynamic Bias Switching

A novel bias-switching scheme for a high-efficiency power amplifier is proposed. Two voltage levels for the drain bias of the RF power amplifier are generated using a combination of a class E dc/ac inverter and a class E rectifier with offset voltage. When signal peaks occur, the output of the class E dc/ac inverter is rectified and the rectified dc is added to the offset voltage by the class E rectifier, which boosts the drain bias of the RF power amplifier. Except during peaks, the drain bias of the RF power amplifier is connected to the offset voltage directly. Since the efficiency when there are no peaks is very high due to the direct connection between the offset voltage and drain bias, the overall efficiency of the RF power amplifier can be improved dramatically in high peak-to-average power ratio (PAPR) systems. The measured results show that the drain bias of the RF power amplifier is boosted up to approximately 1.8 times the offset voltage when the RF peaks generate. The overall efficiency of the proposed bias-switching amplifier is improved by 62% compared to that of the fixed bias amplifier in high PAPR systems     

Modular Layer‐by‐Layer Assembly of Polyelectrolytes,Nanoparticles, and Molecular Catalysts into Solar‐to‐Chemical Energy Conversion Devices

The design and fabrication of solar‐to‐chemical energy conversion devices are enabled through interweaving multiple components with various morphologies and unique functions using a versatile layer‐by‐layer assembly method. Cationic and anionic polyelectrolytes are used as an electrostatic adhesive to assemble the following functional materials: plasmonic Ag nanoparticles for improved light harvesting, upconversion nanoparticles for utilization of near‐infrared light, and polyoxometalate water oxidation catalysts for enhanced catalytic activity. Polyelectrolytes also have an additional function of passivating the surface recombination centers of the underlying photoelectrode. These functional components are precisely assembled on a model photoanode (e.g., Fe₂O₃ and BiVO₄) in a desired order and various combinations without degradation of their intrinsic properties. As a result, the performance of water oxidation photoanodes is synergistically enhanced. This study can enable the design and fabrication of novel solar‐to‐chemical energy conversion devices.     

Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice

Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl⁻ currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl⁻ transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.     

VI-116, A Novel Potent Inhibitor of VRAC with Minimal Effect on ANO1

Volume-regulated anion channel (VRAC) is ubiquitously expressed and plays a pivotal role in vertebrate cell volume regulation. A heterologous complex of leucine-rich repeat containing 8A (LRRC8A) and LRRC8B-E constitutes the VRAC, which is involved in various processes such as cell proliferation, migration, differentiation, intercellular communication, and apoptosis. However, the lack of a potent and selective inhibitor of VRAC limits VRAC-related physiological and pathophysiological studies, and most previous VRAC inhibitors strongly blocked the calcium-activated chloride channel, anoctamin 1 (ANO1). In the present study, we performed a cell-based screening for the identification of potent and selective VRAC inhibitors. Screening of 55,000 drug-like small-molecules and subsequent chemical modification revealed 3,3′-((2-hydroxy-3-methoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (VI-116), a novel potent inhibitor of VRAC. VI-116 fully inhibited VRAC-mediated I⁻ quenching with an IC₅₀ of 1.27 ± 0.18 μM in LN215 cells and potently blocked endogenous VRAC activity in PC3, HT29 and HeLa cells in a dose-dependent manner. Notably, VI-116 had no effect on intracellular calcium signaling up to 10 μM, which completely inhibited VRAC, and showed high selectivity for VRAC compared to ANO1 and ANO2. However, DCPIB, a VRAC inhibitor, significantly affected ATP-induced increases in intracellular calcium levels and Eact-induced ANO1 activation. In addition, VI-116 showed minimal effect on hERG K⁺ channel activity up to 10 μM. These results indicate that VI-116 is a potent and selective VRAC inhibitor and a useful research tool for pharmacological dissection of VRAC.