Metabolic bariatric surgery generates substantial, sustained weight loss and health improvement in a real-world setting.

Background: To determine if the positive outcomes from clinical trials regarding the safety and efficacy of metabolic bariatric surgery are reproducible at a national level.

Methods: A longitudinal registry-based observation study with data collected from all persons undergoing metabolic bariatric surgery in Australia from 28 February 2012-31 December 2021 including data from 122,567 index patients who underwent 134,625 completed bariatric procedures.

Main Outcomes And Measures: Defined adverse outcomes at 90-days (unplanned readmission, intensive care admission and re-operation; death), annual change in weight (percent total body weight loss (TBWL)), diabetes treatment and need for re-operation.

Outcome of Retinoblastoma After Implementation of National Retinoblastoma Treatment Guidelines in South Africa.

Purpose: Retinoblastoma, a curable childhood cancer, has been identified as a tracer cancer in the WHO Global Initiative for Childhood Cancer. To document the outcomes of children with retinoblastoma in South Africa, treated as per the first prospective standard national treatment guidelines for childhood cancer in South Africa.

Patients And Methods: All children diagnosed with retinoblastoma between 2012 and 2016 in five South African pediatric oncology units were treated with a standard treatment on the basis of the International Society of Pediatric Oncology-Pediatric Oncology in Developing Countries guidelines for high-income settings.

Importance of PLD2 in an IL-23 driven psoriasiform dermatitis model and potential link to human psoriasis.

Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)-23-induced mouse model of psoriasiform dermatitis.

Soy Protein Containing Diet Attenuates Murine Drug Exposure and Activity via Hepatic and Intestinal Cytochrome P450 Induction.

Pharmacokinetic variability in drug plasma exposure between different studies within the same species is not unexpected due to a variety of factors (such as differences in formulation, active pharmaceutical ingredient salt form and solid-state, genetic strain, sex, environmental, disease status, bioanalysis methods, circadian rhythms, etc.) although variability from within the same research group typically does not occur to a great degree because these variables are commonly controlled. Surprisingly, a pharmacology proof of concept study with a previously validated tool compound from the literature failed to show expected response in murine glucose-6-phosphate isomerase-induced arthritis model which was tied to compound plasma exposure unexpectedly 10-fold lower than exposure observed from early pharmacokinetic study confirming adequate exposure prior to proof of concept.

Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs.

Cytokine induced 3-D organotypic psoriasis skin model demonstrates distinct roles for NF-κB and JAK pathways in disease pathophysiology.

Psoriasis vulgaris is an inflammatory skin disease that affects 2%-3% of the population worldwide. One of the major challenges in discovering novel therapies is the poor translatability of animal models to human disease. Therefore, it is imperative to develop human preclinical models of psoriasis that are amenable to pharmacological intervention.

Clinical Acceptability of Automated Radiation Treatment Planning for Head and Neck Cancer Using the Radiation Planning Assistant.

Purpose: Radiation treatment planning for head and neck cancer is a complex process with much variability; automated treatment planning is a promising option to improve plan quality and efficiency. This study compared radiation plans generated from a fully automated radiation treatment planning system to plans generated manually that had been clinically approved and delivered.

Methods And Materials: The study cohort consisted of 50 patients treated by a specialized head and neck cancer team at a tertiary care center.

ACT1 Is Required for Murine IL-23-Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity.

Psoriasis is a debilitating skin disease characterized by epidermal thickening, abnormal keratinocyte differentiation, and proinflammatory immune cell infiltrate into the affected skin. IL-17A plays a critical role in the etiology of psoriasis. ACT1, an intracellular adaptor protein and a putative ubiquitin E3 ligase, is essential for signal transduction downstream of the IL-17A receptor.

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.

Histologic progression of acne inversa/hidradenitis suppurativa: Implications for future investigations and therapeutic intervention.

Since first recognized in 1839, the pathogenesis of acne inversa (AI) has undergone repeated revisions. Although there is agreement that AI involves occlusion of hair follicles with subsequent inflammation and the formation of tracts, the histologic progression of this disease still requires refinement. The objective of this study was to examine the histologic progression of AI based on the examination of a large cohort of punch biopsies and excisional samples that were examined first by hematoxylin and eosin staining.

Is AJCC/UICC Staging Still Appropriate for Head and Neck Cancers in Developing Countries?

By 2030, 70% of cancers will occur in developing countries. Head and neck cancers are primarily a developing world disease. While anatomical location and the extent of cancers are central to defining prognosis and staging, the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) have incorporated nonanatomic factors that correlate with prognosis into staging (eg, p16 status of oropharyngeal cancers).

Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis.

Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs.

Persistence of Inflammatory Phenotype in Residual Psoriatic Plaques in Patients on Effective Biologic Therapy.

Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess residual plaques despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied 50 subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls.

Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORt.

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) t and its efficacy in preclinical models of psoriasis and arthritis.

Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.

IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate.

Erratum to: Measurement of the boson polarisation in events from collisions at in the lepton + jets channel with ATLAS.

[This corrects the article DOI: 10.1140/epjc/s10052-017-4819-4.].

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin-23 minicircles in mice.

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.

Small Molecule and Pooled CRISPR Screens Investigating IL17 Signaling Identify BRD2 as a Novel Contributor to Keratinocyte Inflammatory Responses.

Interleukin-17A (IL17A) plays a critical role in the development of numerous autoimmune diseases, including psoriasis. The clinical success of IL17A neutralizing biologics in psoriasis has underlined its importance as a drug discovery target. While many studies have focused on the differentiation and trafficking of IL17A producing T-helper 17 cells, less is known about IL17A-initiated signaling events in stromal and parenchymal cells leading to psoriatic phenotypes.

Monocytes/Macrophages play a pathogenic role in IL-23 mediated psoriasis-like skin inflammation.

Psoriasis is an immune-mediated inflammatory skin disease that affects millions worldwide. Studying immune cells involved in psoriasis pathogenesis is essential to identify effective and safe therapeutics for the disease. Using human psoriasis skin, activated macrophages were observed in both lesional and non-lesional skin, but were elevated in lesional skin.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV.

Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery.

Background: Animal models of Psoriasis (PsO) are important for our understanding of the pathophysiology of human disease but rarely manifest all features of the disease. In order to facilitate greater understanding of the underlying biology of PsO it is key that we understand the strengths and limitations of models used.

Objective: While humanized mouse models are available for PsO they remain technically challenging, expensive, require prolonged timelines and require a continued source of human tissue.

Retrospective Validation and Clinical Implementation of Automated Contouring of Organs at Risk in the Head and Neck: A Step Toward Automated Radiation Treatment Planning for Low- and Middle-Income Countries.

Purpose We assessed automated contouring of normal structures for patients with head-and-neck cancer (HNC) using a multiatlas deformable-image-registration algorithm to better provide a fully automated radiation treatment planning solution for low- and middle-income countries, provide quantitative analysis, and determine acceptability worldwide. Methods Autocontours of eight normal structures (brain, brainstem, cochleae, eyes, lungs, mandible, parotid glands, and spinal cord) from 128 patients with HNC were retrospectively scored by a dedicated HNC radiation oncologist. Contours from a 10-patient subset were evaluated by five additional radiation oncologists from international partner institutions, and interphysician variability was assessed.

Measurements of the production cross section of a [Formula: see text] boson in association with jets in collisions at [Formula: see text] TeV with the ATLAS detector.

Measurements of the production cross section of a [Formula: see text] boson in association with jets in proton-proton collisions at [Formula: see text] TeV are presented, using data corresponding to an integrated luminosity of 3.16 fb[Formula: see text] collected by the ATLAS experiment at the CERN Large Hadron Collider in 2015. Inclusive and differential cross sections are measured for events containing a [Formula: see text] boson decaying to electrons or muons and produced in association with up to seven jets with [Formula: see text] GeV and [Formula: see text].

Fiducial, total and differential cross-section measurements of -channel single top-quark production in collisions at 8 TeV using data collected by the ATLAS detector.

Detailed measurements of -channel single top-quark production are presented. They use 20.2 fb[Formula: see text] of data collected by the ATLAS experiment in proton-proton collisions at a centre-of-mass energy of 8 TeV at the LHC.