Processes shaping the spatial pattern and seasonality of the surface air temperature response to anthropogenic forcing

In the period 1960-2010, the land surface air temperature (SAT) warmed more rapidly over some regions relative to the global mean. Using a set of time-slice experiments, we highlight how different physical processes shape the regional pattern of SAT warming. The results indicate an essential role of anthropogenic forcing in regional SAT changes from the 1970s to 2000s, and show that both surface-atmosphere interactions and large-scale atmospheric circulation changes can shape regional responses to forcing. Single forcing experiments show that an increase in greenhouse gases (GHG) can lead to regional changes in land surface warming in winter (DJF) due to snow-albedo feedbacks, and in summer (JJA) due to soil-moisture and cloud feedbacks. Changes in anthropogenic aerosol and precursor (AA) emissions induce large spatial variations in SAT, characterized by warming over western Europe, Eurasia, and Alaska. In western Europe, SAT warming is stronger in JJA than in DJF due to substantial increases in clear sky shortwave radiation over Europe, associated with decreases in local AA emissions since the 1980s. In Alaska, the amplified SAT warming in DJF is due to increased downward longwave radiation, which is related to increased water vapor and cloud cover. In this case, although the model was able to capture the regional pattern of SAT change, and the associated local processes, it did not simulate all processes and anomalies correctly. For the Alaskan warming, the model is seen to achieve the correct regional response in the context of a wider North Pacific anomaly that is not consistent with observations. This demonstrates the importance of model evaluation that goes beyond the target variable in detection and attribution studies

Benefit of Apabetalone on Plasma Proteins in Renal Disease.

Introduction:Apabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has in vitro and in vivo anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease. Chronic kidney disease is associated with a progressive loss of renal function and a high risk of cardiovascular disease. We studied the impact of apabetalone on the plasma proteome in patients with impaired kidney function. Methods:Subjects with stage 4 or 5 chronic kidney disease and matched controls received a single dose of apabetalone. Plasma was collected for pharmacokinetic analysis and for proteomics profiling using the SOMAscan 1.3k platform. Proteomics data were analyzed with Ingenuity Pathway Analysis to identify dysregulated pathways in diseased patients, which were targeted by apabetalone. Results:At baseline, 169 plasma proteins (adjusted P value <0.05) were differentially enriched in renally impaired patients versus control subjects, including cystatin C and β2 microglobulin, which correlate with renal function. Bioinformatics analysis of the plasma proteome revealed a significant activation of 42 pathways that control immunity and inflammation, oxidative stress, endothelial dysfunction, vascular calcification, and coagulation. At 12 hours postdose, apabetalone countered the activation of pathways associated with renal disease and reduced the abundance of disease markers, including interleukin-6, plasminogen activator inhibitor-1, and osteopontin. Conclusion:These data demonstrated plasma proteome dysregulation in renally impaired patients and the beneficial impact of apabetalone on pathways linked to chronic kidney disease and its cardiovascular complications

Treat-to-target in PsA: methods and necessity

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. With increasing recognition of the high burden and impact of psoriatic arthritis (PsA) and the growing number of therapeutic options, there has been an intensifying focus on treatment strategy in recent years. In 2015, the Tight Control of Psoriatic Arthritis study confirmed the clinical benefit of using a treat-to-target approach in PsA. This randomised controlled trial found benefits in both arthritis and psoriasis disease activity as well as lower disease impact reported by patients, although participants allocated to tight control experienced a higher rate of serious adverse events. European and international recommendations support the use of a treat-to-target approach in PsA and have offered specific advice on how to do this using outcomes such as the minimal disease activity criteria. However, implementation of this approach in routine practice is low, with real-world data highlighting undertreatment as a result. Recent qualitative work with physicians in the UK has helped researchers to understand the barriers to implementation of treat-to-target in PsA. We now need to address these barriers, provide education and support to non-specialist clinicians in routine practice, and aid the translation of optimal care to the clinic

The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer

Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy and be involved in breast cancer progression. To date, a small number of enzymes that control methylation status of histones have been identified as co-regulators of ER signalling. We have identified the histone H3 lysine 9 mono- and di-methyl demethylase enzyme KDM3A as a positive regulator of ER activity. Here, we demonstrate that depletion of KDM3A by RNAi abrogates the recruitment of the ER to cis-regulatory elements within target gene promoters, thereby inhibiting estrogen-induced gene expression changes. Global gene expression analysis of KDM3A-depleted cells identified gene clusters associated with cell growth. Consistent with this, we show that knockdown of KDM3A reduces ER-positive cell proliferation and demonstrate that KDM3A is required for growth in a model of endocrine therapy-resistant disease. Crucially, we show that KDM3A catalytic activity is required for both ER-target gene expression and cell growth, demonstrating that developing compounds which target demethylase enzymatic activity may be efficacious in treating both ER-positive and endocrine therapy-resistant disease

Mixed methods study of clinicians' perspectives on barriers to implementation of treat to target in psoriatic arthritis

Objectives: In treat to target (T2T), the patient is treated to reach and maintain specified and sequentially measured goals, such as remission or low disease activity. T2T in psoriatic arthritis (PsA) has demonstrated improved clinical and patient-reported outcomes and is recommended in European guidelines. However, most clinicians do not use T2T in PsA. This study examined the barriers and enablers to implementation in practice. Methods: Sequential mixed methods comprising a qualitative design (interviews and focus group) to inform a quantitative design (survey). Qualitative data were analysed thematically, and quantitative statistics were analysed descriptively. Results: Nineteen rheumatology clinicians participated in telephone interviews or a face-to-face focus group. An overarching theme 'Complexity' (including 'PsA vs Rheumatoid Arthritis', 'Measurement' and 'Resources') and an underpinning theme 'Changes to current practice' (including 'Reluctance due to organisational factors' and 'Individual determination to make changes') were identified. 153 rheumatology clinicians responded to an online survey. Barriers included limited clinical appointment time to collect outcome data (54.5%) and lack of training in assessing skin disease (35%). Enablers included provision of a protocol (86.4%), a local implementation lead (80.9%), support in clinic to measure outcomes (83.3%) and training in T2T (69.8%). The importance of regular audit with feedback, specialist PsA clinics and a web-based electronic database linked to hospital/national information technology (IT) systems were also identified as enablers. Conclusions: Implementation of T2T in PsA requires an integrated approach to address the support, training and resource needs of individual clinicians, rheumatology teams, local IT systems and service providers to maximise success