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.

A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis.

Background: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Methods: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.

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.

An Epistolary Conversation.

This written exchange is between a senior and a younger Jungian analyst on issues relevant to the development of analytical psychology throughout the world today. The younger analyst, Stefano Carpani, considers himself a neo-Jungian. He explains to John Beebe, known for post-Jungian contributions to the study of typology, integrity, and gender, how important it is to include sociological perspectives alongside those that stem from the Jungian practice of relational psychoanalysis.

Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation.

Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance frequently occurs and is a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown.

Efficacy and Safety of the TYK2/JAK1 Inhibitor Brepocitinib for Active Psoriatic Arthritis: A Phase IIb Randomized Controlled Trial.

Objective: Brepocitinib is a TYK2/JAK1 inhibitor in development for the treatment of several immunologic diseases. The efficacy and safety of oral brepocitinib were assessed in participants with moderately-to-severely active psoriatic arthritis (PsA) for up to 52 weeks.

Methods: In this placebo-controlled, dose-ranging, phase IIb study, participants were randomized to receive 10 mg, 30 mg, or 60 mg of brepocitinib once daily or placebo, advancing to 30 mg or 60 mg of brepocitinib once daily at week 16.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

Background: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways.

Objectives: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO.

Methods: This phase IIb multicentre randomized double-blind study was conducted in two stages.

Therapeutic Activity of the Lansoprazole Metabolite 5-Hydroxy Lansoprazole Sulfide in Triple-Negative Breast Cancer by Inhibiting the Enoyl Reductase of Fatty Acid Synthase.

Fatty acid synthase (FASN), a sole cytosolic enzyme responsible for de-novo lipid synthesis, is overexpressed in cancer but not in normal non-lipogenic tissues. FASN has been targeted, albeit no such inhibitor has been approved. Proton pump inhibitors (PPIs), approved for digestive disorders, were found to inhibit FASN with anticancer activities in attempting to repurpose Food and Drug Administration-approved drugs.

Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study.

Background: Atopic dermatitis (AD) is a prevalent inflammatory, pruritic skin disease. The Janus kinase (JAK) pathway is a treatment target.

Objectives: To assess the efficacy, safety and pharmacokinetics of topical cream brepocitinib, a small-molecule tyrosine kinase 2 (TYK2)/JAK1 inhibitor, in participants with mild-to-moderate AD.

Characterizing the Dose Response of Hyperoxia with Brain Perfusion.

Tactical aviators require administration of enhanced inspired oxygen concentrations (hyperoxia) to reduce risk of hypobaric hypoxia and decompression injuries. Hyperoxia is not without consequence; it reduces cerebral perfusion (CBF). Characterizing the relationship between FO₂ and CBF is necessary to establish FO₂ levels that do not reduce CBF yet are sufficient to mitigate risk of in-flight physiological stressors.

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 transcendent function in Spitteler's Prometheus and Epimetheus.

In August 2020, John Beebe and Steve Myers met via Zoom to discuss their differing interpretations of psychological typology and the different sources within Jung's writings that influenced their books: Integrity in Depth: Energies and Patterns in Psychological Type (Beebe), and Myers-Briggs Typology vs Jungian Individuation (Myers). The discussion centred on Spitteler's epic poem Prometheus und Epimetheus, which forms the basis of chapter V of Psychological Types. This is both the largest chapter and one of two chapters that Jung highlighted in the Argentine foreword as containing the essence of the book.

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.

Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Infants with Congenital Diaphragmatic Hernia: A Novel Tool for Direct Assessment of Severity of Pulmonary Hypertension and Hypoplasia.

Objectives: To assess the feasibility of magnetic resonance imaging (MRI) for postnatal assessment of pulmonary vascularity in infants with congenital diaphragmatic hernia (CDH).

Study Design: Infants with prenatally diagnosed CDH (n = 24) received postnatal pulmonary MRI. Infants with nonpulmonary birth defects served as controls (n = 5).

Determining Compositional Variation in Silicon-Metal Alloys by Parsing SEM/EDS Hyperspectral Images.

High-temperature differential scanning calorimetry was used to understand the thermal properties of Si-rich metal–silicon alloys. Insoluble metals (A and B) were found to produce an alloy with discrete ASi2 and BSi2 dispersed phases. In contrast, metals that form a solid solution result in a dispersed phase that has a composition of AxB1−xSi2, where x varies continuously across each inclusion.

Patient-Reported Symptoms and Disease Impacts in Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Phase 2b Study With Abrocitinib.

Background: Moderate-to-severe atopic dermatitis (AD) is inadequately controlled with current treatments for many patients. Abrocitinib is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of AD.

Objective: The aim of the study was to evaluate patient-reported outcomes in a phase 2b study of abrocitinib in adults with moderate-to-severe AD inadequately controlled by topical therapy (NCT02780167).

Non-Fluorinated, Superhydrophobic Binder-Filler Coatings on Smooth Surfaces: Controlled Phase Separation of Particles to Enhance Mechanical Durability.

There has been a recent drive to develop non-fluorinated superhydrophobic coatings due to the toxicity, cost, and environmental impact of perfluorinated components. One of the main challenges in developing superhydrophobic coatings in general and non-fluorinated superhydrophobic coatings in particular is optimization of mechanical durability, as the rough asperities required for maintaining superhydrophobicity tend to be easily removed by abrasion. Although rough and self-similar hydrophobic surfaces composed of loosely adhered particles or highly porous structures tend to produce excellent superhydrophobicity, they have low inherent mechanical durability and their longevity under real conditions is compromised.

Corrigendum: eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation.

[This corrects the article DOI: 10.3389/fcell.2020.

Gait Variability and Relationships With Fear, Avoidance, and Pain in Adolescents With Chronic Pain.

Objective: Some children with chronic pain struggle with fear of pain, avoidance behaviors, and associated disability; however, movement adaptations in the context of chronic pain in childhood is virtually unknown. Variability in adaptive movement responses previously observed between individuals might be largely explained by the presence of problematic psychological drivers (eg, fear, avoidance). The goals of this study were to quantify the variability of gait and examine relationships among pain, fear, avoidance, function (perceived and objective), and gait variability.

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

Background: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized.

eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation.

Translation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR).