Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy.

We analyzed the role of pro- and anti-inflammatory eicosanoids in the pathogenesis of arrhythmogenic cardiomyopathy (ACM). Lipidomics revealed reduced levels of anti-inflammatory oxylipins in plasma and increased levels of pro-inflammatory eicosanoids in hearts of Dsg2 mice, a preclinical model of ACM. Disease features were reversed in vitro in rat ventricular myocytes expressing mutant JUP by the anti-inflammatory epoxyeicosatrienoic acid 14-15-EET, whereas 14,15-EEZE, which antagonizes the 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin.

Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy.

Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of mice, a well characterized mouse model of ACM.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes.

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase.

Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation.

A Review of Scheduling Strategies for Radiotherapy and Immune Checkpoint Inhibition in Locally Advanced Rectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy across the globe and, despite advances in treatment strategies, survival rates remain low. Rectal cancer (RC) accounts for most of these cases, and traditional management strategies for advanced disease include total neoadjuvant therapy (TNT) with chemoradiotherapy followed by curative surgery. Unfortunately, approximately 10-15% of patients have no response to treatment or have recurrence at a short interval following radiotherapy.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues.

Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy.

Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of and stroma-rich models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours.

Adherence by orthopaedic surgeons to AHPRA and Australian Orthopaedic Association advertising guidelines.

Objectives: To examine adherence to Australian Health Practitioner Regulation Agency (AHPRA) and Australian Orthopaedic Association (AOA) advertising guidelines by AOA members.

Design, Setting: Cross-sectional survey, Australia.

Participants: Two samples of AOA member orthopaedic surgeons: 81 randomly selected from a list of AOA members with publicly available contact details (AOA random sample); and a sample obtained by searching with Google for "orthopaedic surgeon" and the name of the major city in each of the eight Australian states and territories in turn; the top eight results for each search were considered for inclusion (AOA Google sample).

Pre-clinical modelling of rectal cancer to develop novel radiotherapy-based treatment strategies.

Pre-operative chemoradiotherapy reduces local recurrence rates in locally advanced rectal cancer. 10-20% of patients undergo complete response to chemoradiotherapy, however, many patients show no response. The mechanisms underlying this are poorly understood; identifying molecular and immunological factors underpinning heterogeneous responses to chemoradiotherapy, will promote development of treatment strategies to improve responses and overcome resistance mechanisms.

A Pharmacokinetic Bioequivalence Study of Fremanezumab Administered Subcutaneously Using an Autoinjector and a Prefilled Syringe.

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing.

CyanoGate: A Modular Cloning Suite for Engineering Cyanobacteria Based on the Plant MoClo Syntax.

Recent advances in synthetic biology research have been underpinned by an exponential increase in available genomic information and a proliferation of advanced DNA assembly tools. The adoption of plasmid vector assembly standards and parts libraries has greatly enhanced the reproducibility of research and the exchange of parts between different labs and biological systems. However, a standardized modular cloning (MoClo) system is not yet available for cyanobacteria, which lag behind other prokaryotes in synthetic biology despite their huge potential regarding biotechnological applications.

Bioequivalence of fluticasone propionate and salmeterol (FS) given by the FS Spiromax® and Seretide Accuhaler® systems .

Objective: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 µg and Seretide Accuhaler 50/500 µg inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed.

Materials And Methods: In two single-center, open-label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ and Pearson r values were calculated for PD (maximum effect [E ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [C ], time to C [T ], and abuse quotient [PK AQ; C /T ]) for all treatments.

Pharmacokinetics of Beclomethasone Dipropionate Delivered by Breath-Actuated Inhaler and Metered-Dose Inhaler in Healthy Subjects.

Background: Breath-actuated inhalers (BAIs) eliminate the need for hand-breath coordination required of pressurized metered-dose inhalers (MDIs). This pharmacokinetic study compared systemic exposure following beclomethasone dipropionate delivery through BAI versus MDI.

Methods: This open-label, three-period crossover, single-dose study randomized healthy subjects aged 18-45 years (N = 72) to 1 of 6 treatment sequences containing beclomethasone dipropionate BAI 160 mcg (40 mcg/inhalation, 4 inhalations), beclomethasone dipropionate BAI 320 mcg (80 mcg/inhalation, 4 inhalations), and beclomethasone dipropionate MDI 320 mcg (80 mcg/inhalation, 4 inhalations).

Evaluation of beclomethasone dipropionate (80 and 160 micrograms/day) delivered a breath-actuated inhaler for persistent asthma.

Background: Breath-actuated inhalers (BAI) may simplify the delivery of inhaled medications compared with other devices.

Objective: To evaluate the efficacy and safety of beclomethasone dipropionate BAI versus matching placebo in adolescent and adult patients with persistent asthma.

Methods: This phase III, 12-week, double-blind study enrolled patients with asthma aged ≥12 years who were previously treated with a stable dose of inhaled corticosteroid or noncorticosteroid therapy.

Safety, efficacy, and dose response of fluticasone propionate delivered via the novel MDPI in patients with severe asthma: A randomized, controlled, dose-ranging study.

Objective: Evaluate fluticasone propionate (Fp) using a novel, inhalation-driven, multidose dry powder inhaler (MDPI) in patients with severe persistent asthma, versus placebo MDPI and Fp dry powder inhaler (DPI).

Methods: Patients with persistent asthma despite use of high-dose inhaled corticosteroids were randomized to Fp MDPI 50, 100, 200, or 400 mcg; Fp DPI 250 mcg; or placebo MDPI twice daily for 12 weeks. The primary outcome measure was change from baseline in trough forced expiratory volume in 1 second (FEV) over the 12-week period, compared with placebo; secondary measures included change from baseline in peak expiratory flow (PEF), rescue inhaler use, and time to withdrawal due to meeting stopping criteria.

Peripheral Nerve Blocks Causing Increased Risk for Fall and Difficulty in Ambulation for the Hip and Knee Joint Replacement Patient.

A systematic review of the literature was completed by the Evidence-Based Practice Group for the Patient population, Intervention/Issue, Comparison Intervention, Outcomes, Timing (PICOT) question: "Does the use of a peripheral nerve block increase the risk for falls and difficulty ambulation in patients after lower extremity surgery through postoperative day 2?" A search of multiple databases using specified key terms resulted in 258 articles for total knee arthroplasty or total hip arthroplasty. These were reduced to 13 with exclusion criteria and became primary evidence. Numbers Needed to Harm and Numbers Needed to Treat (NNT) were calculated.

Randomized, dose-ranging study of a fluticasone propionate multidose dry powder inhaler in adolescents and adults with uncontrolled asthma not previously treated with inhaled corticosteroids.

Objective: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) eliminates the need to coordinate actuation with inhalation. To characterize dose response, efficacy, and safety of fluticasone propionate (Fp) MDPI, a dose-ranging study was conducted with placebo and active comparators.

Methods: This 12-week, double-blind, parallel-group study randomized patients aged ≥12 years with uncontrolled persistent asthma not previously treated with inhaled corticosteroid therapy (N = 622) to twice-daily treatment with Fp MDPI (12.

Pharmacokinetics, Safety, and Tolerability of a New Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone Propionate Diskus(®) in Healthy Adults.

Background: Fluticasone propionate (Fp) is an inhaled corticosteroid with well-established safety and efficacy profiles. This study evaluated the systemic pharmacokinetics of Fp inhaled from a novel, inhalation-driven multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation.

Methods: This was a single-center, open-label, randomized, 3-period crossover, single-dose study in healthy Japanese and Caucasian subjects aged 20-45 years, inclusive.

Pharmacokinetics of fluticasone propionate multidose, inhalation-driven, novel, dry powder inhaler versus a prevailing dry powder inhaler and a metered-dose inhaler.

Background: A novel inhalation-driven multidose dry powder inhaler (MDPI) that eliminates the need for the patient to coordinate device actuation with inhalation has been developed for delivery of inhaled asthma medications.

Objective: To characterize the pharmacokinetics of single-dose fluticasone propionate (Fp) MDPI compared with single doses of Fp dry powder inhaler (DPI) and a metered-dose inhaler (MDI) in healthy subjects.

Methods: This was a single-center, open-label, randomized, three-period crossover, single-dose pilot study in healthy adults ages 18 to 45 years.

A six-year follow-up study of social network changes among African-American, Caribbean, and U.S.-born Caucasian urban older adults.

This study explores dynamic changes in network size and composition by examining patterns of older adults' social network change over time, that is: types of movements; the reason for the loss of network members; and the relation of movement and composition in concert. This study is a 6-year follow up of changes in the social networks of U.S.

Coiled-coil protein Scy is a key component of a multiprotein assembly controlling polarized growth in Streptomyces.

Polarized growth in eukaryotes requires polar multiprotein complexes. Here, we establish that selection and maintenance of cell polarity for growth also requires a dedicated multiprotein assembly in the filamentous bacterium, Streptomyces coelicolor. We present evidence for a tip organizing center and confirm two of its main components: Scy (Streptomyces cytoskeletal element), a unique bacterial coiled-coil protein with an unusual repeat periodicity, and the known polarity determinant DivIVA.

General job stress: a unidimensional measure and its non-linear relations with outcome variables.

This article aims to examine the non-linear relations between a general measure of job stress [Stress in General (SIG)] and two outcome variables: intentions to quit and job satisfaction. In so doing, we also re-examine the factor structure of the SIG and determine that, as a two-factor scale, it obscures non-linear relations with outcomes. Thus, in this research, we not only test for non-linear relations between stress and outcome variables but also present an updated version of the SIG scale.

Image-guided optimization of the ECG trace in cardiac MRI.

Improper electrocardiogram (ECG) lead placement resulting in suboptimal gating may lead to reduced image quality in cardiac magnetic resonance imaging (CMR). A patientspecific systematic technique for rapid optimization of lead placement may improve CMR image quality. A rapid 3 dimensional image of the thorax was used to guide the realignment of ECG leads relative to the cardiac axis of the patient in forty consecutive adult patients.