Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines.

Leaching and transport of technetium from reducing cementitious waste forms in field lysimeters.

Field lysimeters tests examined leaching of technetium-99 (Tc) from two types of cementitious waste forms and found that the presence of blast furnace slag reduced the overall leaching of Tc from the waste form. The two cementitious waste forms were a slag-grout 45%/45%/10% mixture of fly ash, blast furnace slag, and cement, respectively, referred to as slag-grout or a 55%/45% mixture of cement and fly ash, respectively, referred to here simply as cement. Duplicate sources of each composition were buried in four lysimeters for approximately 10 months to evaluate leaching characteristics under natural meteorological conditions in South Carolina, USA.

Mapping Sequential IgE-Binding Epitopes on Major and Minor Egg Allergens.

Introduction: Molecular studies of hen's egg allergens help define allergic phenotypes, with IgE to sequential (linear) epitopes on the ovomucoid (OVM) protein associated with a persistent disease. Epitope profiles of other egg allergens are largely unknown. The objective of this study was to construct an epitope library spanning across 7 allergens and further evaluate sequential epitope-specific (ses-)IgE and ses-IgG4 among baked-egg reactive or tolerant children.

Accurate and reproducible diagnosis of peanut allergy using epitope mapping.

Background: Accurate diagnosis of peanut allergy is a significant clinical challenge. Here, a novel diagnostic blood test using the peanut bead-based epitope assay ("peanut BBEA") was developed utilizing the LEAP cohort and then validated using two independent cohorts.

Methods: The development of the peanut BBEA diagnostic test followed the National Academy of Medicine's established guidelines with discovery performed on 133 subjects from the non-interventional arm of the LEAP trial and an independent validation performed on 82 subjects from the CoFAR2 and 84 subjects from the POISED study.

Author Correction: Novel Bead-Based Epitope Assay is a sensitive and reliable tool for profiling epitope-specific antibody repertoire in food allergy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel Bead-Based Epitope Assay is a sensitive and reliable tool for profiling epitope-specific antibody repertoire in food allergy.

Identification of allergenic IgE epitopes is instrumental for the development of novel diagnostic and prognostic methods in food allergy. In this work, we present the quantification and validation of a Bead-Based Epitope Assay (BBEA) that through multiplexing of epitopes and multiple sample processing enables completion of large experiments in a short period of time, using minimal quantities of patients' blood. Peptides that are uniquely coupled to beads are incubated with serum or plasma samples, and after a secondary fluorophore-labeled antibody is added, the level of fluorescence is quantified with a Luminex reader.

CYTOMEGALOVIRUS RETINITIS AFTER AN INTRAVITREAL DEXAMETHASONE IMPLANT IN AN IMMUNOCOMPETENT PATIENT.

Purpose: To present the case of a 71-year-old woman who developed cytomegalovirus retinitis after the administration of an intravitreal dexamethasone implant in an immunocompetent patient.

Methods: Retrospective case report.

Patients: Single patient with a diagnosis of cytomegalovirus retinitis associated with the intravitreal dexamethasone implant.

Structure-Property Basis for Solving Transporter-Mediated Efflux and Pan-Genotypic Inhibition in HCV NS5B Inhibitors.

In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide and the benchmark -ethylamino analog . In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption.

Treatment of Ipilimumab-Induced Vogt-Koyanagi-Harada Syndrome With Oral Dexamethasone.

The author presents a retrospective case report of a 54-year-old male with ipilimumab (Yervoy; Bristol-Myers Squibb, New York City, NY)-induced Vogt-Koyanagi-Harada Disease (VKH), which consisted of uveitis, optic neuritis, and choroiditis that was successfully treated with oral dexamethasone. The patient demonstrated resolution of uveitis, optic neuritis, and choroiditis 1 month following initiation of oral dexamethasone. Ipilimumab is a recently approved therapy for malignant melanoma.

An improved protocol for amino acid type-selective isotope labeling in insect cells.

An improved expression protocol is proposed for amino acid type-specific [C], [N]-isotope labeling of proteins in baculovirus-infected (BV) insect cell cultures. This new protocol modifies the methods published by Gossert et al. (J Biomol NMR 51(4):449-456, 2011) and provides efficient incorporation of isotopically labeled amino acids, with similar yields per L versus unlabeled expression in rich media.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile.

Primary Vitreoretinal Lymphoma: Management of Isolated Ocular Disease.

Background: The prognosis for patients with primary vitreoretinal is dismal. The close association of primary vitreoretinal lymphoma with primary central nervous system lymphoma is responsible for high rates of mortality. Traditional treatments consist of systemic chemotherapy and whole-brain radiotherapy.

Development of a RapidFire mass spectrometry assay and a fluorescence assay for the discovery of kynurenine aminotransferase II inhibitors to treat central nervous system disorders.

Kynurenine aminotransferases convert kynurenine to kynurenic acid and play an important role in the tryptophan degradation pathway. Kynurenic acid levels in brain have been hypothesized to be linked to a number of central nervous system (CNS) disorders. Kynurenine aminotransferase II (KATII) has proven to be a key modulator of kynurenic acid levels in brain and, thus, is an attractive target to treat CNS diseases.

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

Background: A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain.

Polycystic Ovary Syndrome and Central Serous Chorioretinopathy.

The authors report a case series of five women with the diagnosis of polycystic ovary syndrome (PCOS) (n = 4) or a first-degree relative with PCOS (n = 1) who presented with central serous chorioretinopathy (CSR). This report is the first to correlate PCOS and CSR on clinical presentation. Patients with PCOS often exhibit physical evidence of elevated androgens, such as testosterone, which recently has been linked to CSR.

Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach.

Machines and cutters: Constellation®.

The Alcon Constellation® provides state-of-the-art technology for vitrectomy surgery. Its innovative features include utilization of high-speed and small-gauge vitrectomy systems, surgeon-controlled duty cycle, fine intraocular pressure control, and integrated laser and intraocular gas mixing capabilities. The goal of vitrectomy surgery is the safe and efficient removal of vitreous while avoiding iatrogenic retinal tears or iatrogenic incarceration of retinal tissue.

Quantitative measurement of ligand exchange on iron oxides via radiolabeled oleic acid.

Ligand exchange of hydrophilic molecules on the surface of hydrophobic iron oxide nanoparticles produced via thermal decomposition of chelated iron precursors is a common method for producing aqueous suspensions of particles for biomedical applications. Despite the wide use, relatively little is understood about the efficiency of ligand exchange on the surface of iron oxide nanoparticles and how much of the hydrophobic ligand is removed. To address this issue, we utilized a radiotracer technique to track the exchange of a radiolabeled (14)C-oleic acid ligand with hydrophilic ligands on the surface of magnetite nanoparticles.

Central serous chorioretinopathy in patients receiving exogenous testosterone therapy.

Purpose: To report an association between central serous chorioretinopathy (CSCR) and exogenous testosterone therapy.

Methods: This is a retrospective case series from two institutions. Patients who presented with fluorescein angiography and optical coherence tomography findings consistent with CSCR were included.

Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering.

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding.

Characteristics of intraretinal deposits in acute central serous chorioretinopathy.

Purpose: To describe the temporal and spatial characteristics of intraretinal deposits in patients with acute central serous chorioretinopathy (CSC) using spectral domain optical coherence tomography (OCT).

Materials And Methods: We retrospectively reviewed the medical records of all patients that presented with acute CSC to Weill Cornell Medical College from January 2012 to May 2013. Acute CSC was defined as a diagnosis of CSC within 4 months of the onset of symptoms.

High-throughput high-content imaging assays for identification and characterization of selective AXL pathway inhibitors.

Receptor tyrosine kinases (RTKs) regulate a wide range of important biological activities, including cell proliferation, differentiation, migration, and apoptosis. Abnormalities in RTKs are involved in numerous diseases, including cancer and other proliferative disorders. AXL belongs to the TAM (Tyso3, AXL, and Mer) family of RTKs.

Isolated foveal hypoplasia without nystagmus.

We report the case of a 23-year-old healthy Caucasian male with isolated foveal hypoplasia without nystagmus. Clinical examination and spectral-domain optical coherence tomography demonstrated the bilateral absence of a foveal depression and the patient was diagnosed with isolated foveal hypoplasia. This is a rare condition which is probably under-diagnosed since it can exist without nystagmus and low vision.