Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates.

Although peptide motifs represent the majority of cleavable linkers used in clinical-stage antibody-drug conjugates (ADCs), the sequences are often sensitive to cleavage by extracellular enzymes, such as elastase, which leads to systemic release of the cytotoxic payload. This action reduces the therapeutic index by causing off-target toxicities that can be dose-limiting. For example, a common side-effect of ADCs made using peptide-cleavable linkers is myelosuppression, including neutropenia.

A Novel HER2-targeted Antibody-drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels.

Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2 breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload.

High-Performance Green Light-Emitting Diodes Based on MAPbBr with π-Conjugated Ligand.

The morphology, crystal size, and trap density of perovskite films significantly affect the luminescent properties of perovskite light-emitting diodes (PeLEDs). Recently, numerous studies have been conducted on ligands that surround the surface of perovskite crystals and passivate the trap sites to improve the performance of PeLEDs. In this study, a 4-aminobenzonitrile (ABN) ligand improved the performance of methylammonium lead bromide (MAPbBr)-based PeLEDs by reducing the MAPbBr crystal size to the nanoscale and reducing the trap density.

Violet Light-Emitting Diodes Based on p-CuI Thin Film/n-MgZnO Quantum Dot Heterojunction.

As the lighting technology evolves, the need for violet light-emitting diodes (LEDs) is growing for high color rendering index lighting. The present technology for violet LEDs is based on the high-cost GaN materials and metal-organic chemical vapor deposition process; therefore, there have recently been intensive studies on developing low-cost alternative materials and processes. In this study, for the first time, we demonstrated violet LEDs based on low-cost materials and processes using a p-CuI thin film/n-MgZnO quantum dot (QD) heterojunction.

Antibody-drug conjugate library prepared by scanning insertion of the aldehyde tag into IgG1 constant regions.

The advantages of site-specific over stochastic bioconjugation technologies include homogeneity of product, minimal perturbation of protein structure/function, and - increasingly - the ability to perform structure activity relationship studies at the conjugate level. When selecting the optimal location for site-specific payload placement, many researchers turn to in silico modeling of protein structure to identify regions predicted to offer solvent-exposed conjugatable sites while conserving protein function. Here, using the aldehyde tag as our site-specific technology platform and human IgG1 antibody as our target protein, we demonstrate the power of taking an unbiased scanning approach instead.

Effect of Nonionic Surfactant Additive in PEDOT:PSS on PFO Emission Layer in Organic-Inorganic Hybrid Light-Emitting Diode.

Poly(9,9-dioctylfluorene) (PFO) has attracted significant interests owing to its versatility in electronic devices. However, changes in its optical properties caused by its various phases and the formation of oxidation defects limit the application of PFO in light-emitting diodes (LEDs). We investigated the effects of the addition of Triton X-100 (hereinafter shortened as TX) in poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to induce interlayer diffusion between PEDOT:PSS and PFO to enhance the stability of the PFO phase and suppress its oxidation.

Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent.

Coagulation factor XIa is a candidate target for anticoagulants that better separate antithrombotic efficacy from bleeding risk. We report a co-crystal structure of the FXIa protease domain with DEF, a human monoclonal antibody that blocks FXIa function and prevents thrombosis in animal models without detectable increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and active site, while the heavy chain provides electrostatic interactions with the surface of FXIa.

Enhanced Light Stability of InGaZnO Thin-Film Transistors by Atomic-Layer-Deposited YO with Ozone.

We report the effect of YO passivation by atomic layer deposition (ALD) using various oxidants, such as HO, O plasma, and O, on In-Ga-Zn-O thin-film transistors (IGZO TFTs). A large negative shift in the threshold voltage (V) was observed in the case of the TFT subjected to the HO-ALD YO process; this shift was caused by a donor effect of negatively charged chemisorbed HO molecules. In addition, degradation of the IGZO TFT device performance after the O plasma-ALD YO process (field-effect mobility (μ) = 8.

High-Performance Green Light-Emitting Diodes Based on MAPbBr-Polymer Composite Films Prepared by Gas-Assisted Crystallization.

The morphology of perovskite films has a significant impact on luminous characteristics of perovskite light-emitting diodes (PeLEDs). To obtain a highly uniform methylammonium lead tribromide (MAPbBr) film, a gas-assisted crystallization method is introduced with a mixed solution of MAPbBr precursor and polymer matrix. The ultrafast evaporation of the solvent causes a high degree of supersaturation which expedites the generation of a large number of nuclei to form a MAPbBr-polymer composite film with full surface coverage and nano-sized grains.

CAT-02-106, a Site-Specifically Conjugated Anti-CD22 Antibody Bearing an MDR1-Resistant Maytansine Payload Yields Excellent Efficacy and Safety in Preclinical Models.

Hematologically derived tumors make up ∼10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1.

Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis.

Thrombosis is a major cause of morbidity and mortality. Current antithrombotic drugs are not ideal in that they must balance prevention of thrombosis against bleeding risk. Inhibition of coagulation factor XI (FXI) may offer an improvement over existing antithrombotic strategies by preventing some forms of thrombosis with lower bleeding risk.

Low-Temperature Facile Synthesis of Sb-Doped p-Type ZnO Nanodisks and Its Application in Homojunction Light-Emitting Diode.

This study explores low-temperature solution-process-based seed-layer-free ZnO p-n homojunction light-emitting diode (LED). In order to obtain p-type ZnO nanodisks (NDs), antimony (Sb) was doped into ZnO by using a facile chemical route at 120 °C. The X-ray photoelectron spectra indicated the presence of (SbZn-2VZn) acceptor complex in the Sb-doped ZnO NDs.

Efficient identification of human immunodeficiency virus type 1 mutants resistant to a protease inhibitor by using a random mutant library.

Emergence of drug-resistant mutant viruses during the course of antiretroviral therapy is a major hurdle that limits the success of chemotherapeutic treatment to suppress human immunodeficiency virus type 1 (HIV-1) replication and AIDS progression. Development of new drugs and careful patient management based on resistance genotyping data are important for enhancing therapeutic efficacy. However, identifying changes leading to drug resistance can take years of clinical studies, and conventional in vitro assays are limited in generating reliable drug resistance data.

Introducing predetermined mutations throughout a target gene using TDEM (transposon-directed base-exchange mutagenesis).

Transposon-directed base-exchange mutagenesis (TDEM) is an efficient and controllable method for introducing a mutation(s) into a gene. Each round of TDEM removes a predetermined number of bases (up to 11 base pairs) from a randomly selected site within the target gene and replaces them with any length of DNA of predetermined sequence. Therefore, the number of bases to be deleted and inserted can be precisely regulated.

A rapid and economic in-house DNA purification method using glass syringe filters.

Background: Purity, yield, speed and cost are important considerations in plasmid purification, but it is difficult to achieve all of these at the same time. Currently, there are many protocols and kits for DNA purification, however none maximize all four considerations.

Methodology/principal Findings: We now describe a fast, efficient and economic in-house protocol for plasmid preparation using glass syringe filters.

Transposon-directed base-exchange mutagenesis (TDEM): a novel method for multiple-nucleotide substitutions within a target gene.

In this report we describe transposon-directed base-exchange mutagenesis (TDEM), an efficient and controllable method for introducing a mutation into a gene. Each round of TDEM can remove up to 11 base pairs from a randomly selected site within the target gene and replace them with any length of DNA of predetermined sequence. Therefore, the number of bases to be deleted and inserted can be independently regulated providing greater versatility than existing methods of transposon-based mutagenesis.

N-terminal domain-deleted mu transposase exhibits increased transposition activity with low target site preference in modified buffers.

Background: Transposition using MuA and the Mu-transposon is frequently used for insertional and deletional mutagenesis and to introduce primer sequences into DNA of unknown sequence. However, mutagenesis studies are often limited by the number of transposition events taking place within a small target sequence. Although the intrinsic target site preference of MuA is low, it nevertheless may limit the recovery of desired events.

Maspin and p53 protein expression in gastric adenocarcinoma and its clinical applications.

Objectives: To investigate the role of maspin and p53 expression in the progression of gastric cancer, and its value as a prognostic indicator.

Materials And Methods: The expression of maspin and p53 in 152 cases of gastric cancer was detected by immunohistochemistry and compared with the clinicopathologic tumor parameters. The relationship between maspin and p53 expression was also analyzed in the gastric cancers.

Hypotensive effect of butein via the inhibition of angiotensin converting enzyme.

Butein (3,4,2',4'-tetrahydroxychalcone), a plant polyphenol, has been known to elucidate endothelium-dependent vasodilation. In the present study, the hypotensive effect of butein and its possible mechanism, especially an angiotensin converting enzyme (ACE) inhibitory effect, were investigated. Intravenous injection of butein lowered the arterial blood pressure of anesthetized rats in a dose-dependent manner.