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Mei-Chun Yeh,1 Ben J Wu,1 Yue Li,1 Mina Elahy,1 Leonel Prado-Lourenco,1 Jim Sockler,2 Herman Lau,3 Ric O Day,4 Levon M Khachigian1 1Vascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, Australia; 2Statistical Operations & Programming, Datapharm Australia Pty Ltd, Drummoyne, NSW, 2047, Australia; 3BJC Health, Chatswood, NSW, 2067, Australia; 4Department of Clinical Pharmacology & Toxicology, Therapeutics Centre, St Vincent’s Hospital, UNSW Medicine and Health, Darlinghurst, NSW, 2010, AustraliaCorrespondence: Levon M KhachigianVascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, AustraliaTel +61 2 9385 2537Email L.Khachigian@unsw.edu.auIntroduction: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness.Methods: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice.Results: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP+ cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2.Conclusion: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.Keywords: inflammation, pathology, bone erosion, rheumatoid arthritis, dibenzoxazepinone

This study examined the metabolic, thermoregulatory and sympathoadrenal response pattern of eight male subjects to repeated bouts of brief cold stress. Water immersion (WI) was used to induce cold stress over a 60 min period on three separate occasions on three successive days. Rectal temperature (T[sub re]), mean skin temperature (T[sub sk]) and metabolic rate (VO2) were measured at 10 min intervals throughout WI and for 20 min post-immersion (PI). Blood was drawn and assayed for plasma adrenaline (ADR), noradrenaline (NDR) and cortisol at rest, at the end of immersion and PI. Acute cold stress was induced for each of the three exposures with a reduction in T[sub re] of ∼0.63°C (p<0.01) and ∼1.2°C (p<0.01) at the end of immersion and PI, respectively. T[sub sk] was reduced for all trials by ∼6.0°C (p<0.01) at the end of immersion and ∼3.0°C (p<0.01) at PI. VO2 peaked at 40-50 min of WI to 83%, 58% and 47% above rest for each consecutive trial. Plasma ADR did not show any change (p=0.34) as a consequence of cold stress between trials. Plasma NDR increased at the end of immersion (p<0.01) and remained elevated at PI (p<0.01). Plasma cortisol showed no change for any of the exposure periods. ΔT[sub re] was more pronounced for the last exposure and was negatively correlated (r=-0.78, p<0.02) with plasma NDR. The results of this investigation complement previous findings of cold adaptation and suggest a possible adaptive response to repeated brief bouts of cold exposure evidenced by the changing trends in body temperature, metabolic rate and plasma NDR. [ABSTRACT FROM AUTHOR]

Background Previous studies identified factors that modify response to an oral non-typeable Haemophilus influenzae ( NTHi) vaccine in chronic obstructive pulmonary disease ( COPD): severe COPD, moderate-severe exacerbations as end-point and a threshold prevalence of NTHi in the study population. More data are needed to confirm parameters that influence clinical outcomes. Aims The primary aim was to determine the efficacy of an oral NTHi vaccine ( HI-164OV) in reducing the rate of exacerbations requiring systemic corticosteroids or hospitalisation in COPD. Secondary aims included effect on the proportion of patients experiencing such exacerbations, severity of infections and quality of life (St George Respiratory Questionnaire for COPD patients ( SGRQ-C)). Methods This multi-centre, double-blind, placebo-controlled study was conducted at 21 Australian sites for 9 months in 2011. Results Three-hundred and twenty subjects with COPD, FEV1 <60% predicted and ≥1 moderate-severe exacerbations in the previous 12 months were recruited. The primary and secondary end-points for the intention-to-treat population aged 40-88 years were not achieved, and only 5% of subjects had an H. influenzae-positive sputum sample. Subsequent exploratory analysis of patients <65 years (91 subjects) indicated protection with respect to the primary and most of the secondary end-points, with SGRQ-C symptom scores lower at 3 and 6 months. Conclusion Patients aged 40-88 years with moderate to severe COPD and low rates of H. influenzae-positive sputum were not protected against exacerbations by HI-1640V. Further studies are needed to confirm protection in subjects aged <65 years. Older age and low colonisation rates appear to affect adversely response to this vaccine. [ABSTRACT FROM AUTHOR]

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A 165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A 165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Melanoma incidence is increasing worldwide, and although drugs such as BRAF/MEK small-molecule inhibitors and immune checkpoint antibodies improve patient outcomes, most patients ultimately fail these therapies and alternative treatment strategies are urgently needed. DNAzymes have recently undergone clinical trials with signs of efficacy and no serious adverse events attributable to the DNAzyme. Here we investigated c-Jun expression in human primary and metastatic melanoma. We also explored the role of T cell immunity in DNAzyme inhibition of primary melanoma growth and the prevention of growth in non-treated tumors after the cessation of treatment in a mouse model. c-Jun was expressed in 80% of melanoma cells in human primary melanomas (n = 17) and in 83% of metastatic melanoma cells (n = 38). In contrast, c-Jun was expressed in only 11% of melanocytes in benign nevi (n = 24). Dz13, a DNAzyme targeting c-Jun/AP-1, suppressed both Dz13-injected and untreated B16F10 melanoma growth in the same mice, an abscopal effect relieved in each case by administration of anti-CD4/anti-CD8 antibodies. Dz13 increased levels of cleaved caspase-3 within the tumors. New, untreated melanomas grew poorly in mice previously treated with Dz13. Administration of anti-CD4/anti-CD8 antibodies ablated this inhibitory effect and the tumors grew rapidly. Dz13 inhibited c-Jun expression, reduced intratumoral vascularity (vascular lumina area defined by CD31 staining), and increased CD4 + cells within the tumors. This study provides the first demonstration of an abscopal effect of a DNAzyme on tumor growth and shows that Dz13 treatment prevents growth of subsequent new tumors in the same animal. Dz13 may be useful clinically as a therapeutic antitumor agent by preventing tumor relapse through adaptive immunity.

Introduction: This article outlines the current Australian multidisciplinary treatment of synchronous metastatic colorectal adenocarcinoma and assesses the factors that influence patient outcome., Methods: This is a retrospective analysis of the prospective 'Treatment of Recurrent and Advanced Colorectal Cancer' registry, describing the patient treatment pathway and documenting the extent of disease, resection of the colorectal primary and metastases, chemotherapy and biological therapy use. Cox regression models for progression-free and overall survival were constructed with a comprehensive set of clinical variables. Analysis was intentionn-ton-treat, quantifying the effect of treatment intent decided at the multidisciplinary team meeting (MDT)., Results: One thousand one hundred and nine patients presented with synchronous metastatic disease between July 2009 and November 2015. Median follow-up was 15.8 months; 4.4% (group 1) had already curative resections of primary and metastases prior to MDT, 22.2% (group 2) were considered curative but were referred to MDT for opinion and/or medical oncology treatment prior to resection and 70.2% were considered palliative at MDT (group 3). Overall, 83% received chemotherapy, 55% had their primary resected and 23% had their metastases resected; 13% of resections were synchronous, 20% were staged with primary resected first and 62% had only the colorectal primary managed surgically. Performance status, metastasis resection (R0 versus R1 versus R2 versus no resection), resection of the colorectal primary and treatment intent determined at MDT were the most significant factors for progression-free and overall survival., Conclusions: This is the largest Australian series of synchronous metastatic colorectal adenocarcinoma and offers insight into the nature and utility of contemporary practice., (© 2016 Royal Australasian College of Surgeons.)

Aims: Acute coronary syndrome (ACS) is a costly condition for health service provision yet variation in the delivery of care between hospitals persists. A composite measure of adherence with evidence-based clinical-process indicators (CPIs) could better inform hospital performance reporting and clinical outcomes in the management of ACS., Methods: Data on 7444 ACS patients from 39 Australian hospitals were used to derive a hospital-specific composite quality score by calculating mean adherence to 14 evidence-based CPIs. Using the generalized estimating equation to account for clustering of patients within hospitals and the GRACE risk score to adjust for differences in presenting risk, we evaluated associations between the hospital-specific composite quality score, in-hospital major adverse events, in-hospital mortality and mortality and readmission for ACS at 6 months., Results: Hospitals had a mean adherence of 68.3% (SD 21.7) with the composite quality score. There was significant variation between hospital adherence tertile 1 (79%) and tertile 3 (56%), P < 0.0001. With risk adjustment, there was an association between hospitals with a higher composite quality score and reduced in-hospital adverse events (OR: 0.85, CI: 0.71-0.99) and survival at hospital discharge (OR: 0.47; 95% CI: 0.28-0.77). There was trending improvement in survival at 6 months (OR 0.48; CI: 0.20-1.16) and fewer readmissions to hospital for ACS at 6 months (OR 0.79; CI 0.60-1.05)., Conclusion: The association between the quality composite score and reduced in-hospital events and survival at hospital discharge supports the utility of reporting CPIs in routine hospital performance reporting on the management of ACS., Australia and New Zealand Clinical Trial Registration (anzctr): CONCORDANCE Registry ACTRN12614000887673., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Previous studies have shown that arm cranks and arm levers, working as propulsion mechanisms for nonambulatory individuals, may have mechanical and physiologic advantages over standard handrim wheelchairs. This study evaluated physiologic responses to arm lever and arm crank ergometry using identical workloads. An arm lever ergometer (ALE) was constructed and adapted to an arm crank ergometer (ACE) so that equal workloads could be applied with both ergometers. Fifteen able-bodied men and 15 able-bodied women exercised at a low (15 watts) and a high (45 watts) workload, with a three-minute rest interval. While exercising at each level, oxygen consumption (VO2), minute ventilation (VE), and heart rate (HR) were monitored. When low workloads with ALE and ACE were compared, no significant differences (p greater than 0.05) were demonstrated in any of the variables for men or women. For the men, at the high workload, the ALE elicited significantly lower (p less than 0.05) VO2 (by 9.8%), HR (by 6.3%), and VE (by 7.5%), than did the ACE. For the women, at the high workload, VO2 was significantly lower (p less than 0.05) (by 7.6%) with the ALE, as was VE (by 7.5%), but HR, although 3.3% lower with the ALE, was not significantly different (p greater than 0.05) from the ACE. These data suggest that the ALE is physiologically less stressful than the ACE at high workloads. Arm levers may, therefore, provide an advantage for handicapped persons when they propel themselves in wheelchairs.