Exploratory pharmacodynamics and efficacy of PF-06817024 in a Phase 1 study of patients with chronic rhinosinusitis and atopic dermatitis.

PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP.

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60).

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PF-06817024 in Healthy Participants, Participants with Chronic Rhinosinusitis with Nasal Polyps, and Participants with Atopic Dermatitis: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study.

PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF-06817024 doses in healthy participants (Part 1), a single dose of PF-06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF-06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF-06817024 was generally well tolerated in all participant populations.

Toward low-loss mid-infrared GaO-BaO-GeO optical fibers.

The development of efficient and compact photonic systems in support of mid-infrared integrated optics is currently facing several challenges. To date, most mid-infrared glass-based devices are employing fluoride or chalcogenide glasses (FCGs). Although the commercialization of FCGs-based optical devices has rapidly grown during the last decade, their development is rather cumbersome due to either poor crystallization and hygroscopicity resilience or poor mechanical-thermal properties of the FCGs.

Spatial beam reshaping and large-band nonlinear conversion in rectangular-core phosphate glass fibers.

Here we present the ability of Nd-doped zinc-phosphate glasses to be shaped into rectangular core fibers. At first, the physico-chemical properties of the developed PO-based materials are investigated for different concentrations of neodymium oxide and core and cladding glass compositions are selected for further fiber development. A modified stack-and-draw technique is used to produce multimode large rectangular-core optical fibers.

Response of Various Yb-Doped Oxide Glasses to Different Radiation Treatments.

The radiation effects of electrons and protons on the spectroscopic and optical properties of oxide glasses doped with Yb in various glass systems were investigated to understand the impact of the glass composition on the glass photo-response. Changes in the optical and emission properties were seen after the radiation treatment, and the magnitude of the changes depended on the irradiation source and dose. For all the investigated materials, the absorption coefficients in the 200-550 nm range increase post-irradiation, revealing the formation of defects in the glasses during the irradiation.

A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a C-Microtracer Approach.

Zimlovisertib (PF-06650833) is a selective, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with anti-inflammatory effects. This phase 1, open-label, fixed-sequence, two-period, single-dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a C-microtracer approach. All six participants received 300 mg C-zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and C-zimlovisertib 135 μg intravenously (IV) in Period B.

The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.

Objective: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting.

Methods: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs.

Inorganic Thermoelectric Fibers: A Review of Materials, Fabrication Methods, and Applications.

Thermoelectric technology can directly harvest the waste heat into electricity, which is a promising field of green and sustainable energy. In this aspect, flexible thermoelectrics (FTE) such as wearable fabrics, smart biosensing, and biomedical electronics offer a variety of applications. Since the nanofibers are one of the important constructions of FTE, inorganic thermoelectric fibers are focused on here due to their excellent thermoelectric performance and acceptable flexibility.

Transparent Glasses and Glass-Ceramics in the Ternary System TeO-NbO-PbF.

Transparent fluorotellurite glasses were prepared by melt-quenching in the ternary system TeO-NbO-PbF. The synthesis conditions were adjusted to minimize fluorine loss monitored as HF release. It was found that 10 mol% of NbO is the optimum content for PbF incorporation up to 35 mol% in the tellurite matrix without loss of glass forming ability.

Radiation-Induced Defects and Effects in Germanate and Tellurite Glasses.

This review focuses on the radiation-induced changes in germanate and tellurite glasses. These glasses have been of great interest due to their remarkable potential for photonics, in terms of extended transmission window in the mid-infrared, ability of rare-earth loading suitable with a laser, and amplification in the near- and mid-infrared or high nonlinear optical properties. Here, we summarize information about possible radiation-induced defects, mechanisms of their formation, and the influence of the glass composition on this process.

Optical Emission Detector Based on Plasma Discharge Generation at the Tip of a Multimaterial Fiber.

Experimental development of a compact optical emission detector based on the assembly of a polymer-metal and a standard silica fiber is presented in this paper. This device is exploited in a proof-of-principle experiment for gas detection application by means of plasma spectroscopy in the visible-Near Infrared spectral region. A multimode fiber (MMF) is associated with a functional hollow dual-electrodes elongated structure fabricated by the direct preform-to-fiber homothetic co-drawing.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.

Background: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.

Methods: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states.

Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly controlled asthmatics.

Background: A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control.

Direct laser writing of a new type of waveguides in silver containing glasses.

Direct laser writing in glasses is a growing field of research in photonics since it provides a robust and efficient way to directly address 3D material structuring. Generally, direct laser writing in glasses induces physical modifications such as refractive index changes that have been classified under three different types (Type I, II & III). In a silver-containing zinc phosphate glass, direct laser writing additionally proceeds via the formation of silver clusters at the periphery of the interaction voxel.

Demonstration of mid-infrared waveguide photonic crystal cavities.

We have demonstrated what we believe to be the first waveguide photonic crystal cavity operating in the mid-infrared. The devices were fabricated from Ge23Sb7S70 chalcogenide glass (ChG) on CaF2 substrates by combing photolithographic patterning and focused ion beam milling. The waveguide-coupled cavities were characterized using a fiber end fire coupling method at 5.

Demonstration of high-Q mid-infrared chalcogenide glass-on-silicon resonators.

We demonstrated high-index-contrast, waveguide-coupled As2Se3 chalcogenide glass resonators monolithically integrated on silicon fabricated using optical lithography and a lift-off process. The resonators exhibited a high intrinsic quality factor of 2×10(5) at 5.2 μm wavelength, which is among the highest values reported in on-chip mid-infrared (mid-IR) photonic devices.

Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment-motivated heavy smokers.

Rationale: The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome.

Objectives: This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design.

Methods: Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-min intervals.

Resolving optical illumination distributions along an axially symmetric photodetecting fiber.

Photodetecting fibers of arbitrary length with internal metal, semiconductor and insulator domains have recently been demonstrated. These semiconductor devices exhibit a continuous translational symmetry which presents challenges to the extraction of spatially resolved information. Here, we overcome this seemingly fundamental limitation and achieve the detection and spatial localization of a single incident optical beam at sub-centimeter resolution, along a one-meter fiber section.

Fiber field-effect device via in situ channel crystallization.

The in situ crystallization of the incorporated amorphous semiconductor within the multimaterial fiber device yields a large decrease in defect density and a concomitant five-order-of-magnitude decrease in resistivity of the novel metal-insulator-crystalline semiconductor structure. Using a post-drawing crystallization process, the first tens-of-meters-long single-fiber field-effect device is demonstrated. This work opens significant opportunities for incorporating higher functionality in functional fibers and fabrics.

Modulation of pulmonary NA+ pump gene expression during cold storage and reperfusion.

Background: Reperfusion injury with pulmonary edema continues to be a major complication after lung transplantation. Alveolar fluid homeostasis is regulated by Na+/K+-ATPase activity on the basolateral surface of alveolar epithelial cells. Intact Na+/K+-ATPase is essential to the resolution of pulmonary edema.

Integrin alpha(3)-subunit expression modulates alveolar epithelial cell monolayer formation.

We investigated expression of the alpha(3)-integrin subunit by rat alveolar epithelial cells (AECs) grown in primary culture as well as the effects of monoclonal antibodies with blocking activity against the alpha(3)-integrin subunit on AEC monolayer formation. alpha(3)-Integrin subunit mRNA and protein were detectable in AECs on day 1 and increased with time in culture. alpha(3)- and beta(1)-integrin subunits coprecipitated in immunoprecipitation experiments with alpha(3)- and beta(1)-subunit-specific antibodies, consistent with their association as the alpha(3)beta(1)-integrin receptor at the cell membrane.

Epidermal growth factor regulation in adult rat alveolar type II cells of amiloride-sensitive cation channels.

Using the patch-clamp technique, we studied the effects of epidermal growth factor (EGF) on whole cell and single channel currents in adult rat alveolar epithelial type II cells in primary culture in the presence or absence of EGF for 48 h. In symmetrical sodium isethionate solutions, EGF exposure caused a significant increase in the type II cell whole cell conductance. Amiloride (10 microM) produced approximately 20-30% inhibition of the whole cell conductance in both the presence and absence of EGF, such that EGF caused the magnitude of the amiloride-sensitive component to more than double.

Modulation of t1alpha expression with alveolar epithelial cell phenotype in vitro.

T1alpha is a recently identified gene expressed in the adult rat lung by alveolar type I (AT1) epithelial cells but not by alveolar type II (AT2) epithelial cells. We evaluated the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on T1alpha expression using either soluble factors or changes in cell shape to influence phenotype. For studies on the effects of soluble factors on T1alpha expression, rat AT2 cells were grown on polycarbonate filters in serum-free medium (MDSF) or in MDSF supplemented with either bovine serum (BS, 10%), rat serum (RS, 5%), or keratinocyte growth factor (KGF, 10 ng/ml) from either day 0 or day 4 through day 8 in culture.