Intestinal and enthesis innate immunity in early axial spondyloarthropathy

Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the ‘danger signals’ from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

Clinical translation of positive metastases identified on prostate-specific membrane antigen positron emission tomography/computed tomography imaging in the management of de novo synchronous oligometastatic prostate cancer

Recent randomised evidence supports the diagnostic superiority of prostate-specific membrane antigen (PSMA) PET/CT, over conventional imaging, in the detection of distant occult metastasis in men with newly diagnosed high-risk prostate cancer. This may result in a rise in the detection of de novo synchronous hormone-sensitive “oligometastatic” prostate cancer. We outline the evidence supporting PSMA PET/CT imaging in primary staging. We also discuss the translation of positive areas, with a high probability of distant metastasis, into clinical therapeutic targets for metastasis-directed interventions. Finally, we highlight the role of PSMA PET/CT as an imaging biomarker. This may have future utility in disease monitoring and prediction of response to systemic, local cytoreductive and metastasis-directed interventions. Patient Summary: A new whole-body scan can accurately detect cancer deposits, in men in whom distant prostate cancer spread is suspected. This may be useful to monitor and predict response to drug therapy, treatments to the prostate and cancer deposits

BSR Spondyloarthritis Course, 27 February 2020. Spondyloarthritis: pathogenesis, diagnosis and management

High-quality continuous medical education is essential to maintain excellence in health-care delivery, upskilling professionals and improving patient outcomes. This is particularly relevant when addressing rare disease groups, such as the spondyloarthritides, a group of heterogeneous inflammatory conditions that affect joints and other organs, such as the skin, bowel and eye. Professional bodies, such as the British Society for Rheumatology (BSR), are well placed to deliver this type of education. In 2020, the BSR ran a dedicated SpA course aimed at rheumatology health-care professionals wishing to update their basic knowledge of SpA with a review of the latest advances in the field. Here, we summarize the proceedings of the meeting and discuss the value of such an initiative

Chapter 15 - National and sub-national policies and institutions

This chapter assesses national and sub-national mitigation policies and their institutional settings. There has been a marked increase in national policies and legislation on climate change since the AR4 with a diversity of approaches and a multiplicity of objectives (see Section 15.2). However, Figure 1.9 of Chapter 1 suggests that these policies, taken together, have not yet achieved a substantial deviation in emissions from the past trend. Limiting concentrations to levels that would be consistent with a likely probability of maintaining temperature increases below 2 degrees C this century (scenarios generally in the range of 430-480 ppmv CO2eq) would require that emissions break from these trends and be decreased substantially. In contrast, concentrations exceed 1000 ppmv CO2eq by 2100 in many baseline scenarios (that is, scenarios without additional efforts to reduce emissions). The literature on mitigation scenarios provides a wide range of CO2 shadow price levels consistent with these goals, with estimates of less than US$50/tCO2 in 2020 in many studies and exceeding US$100/tCO2 in others, assuming a globally-efficient and immediate effort to reduce emissions. These shadow prices exhibit a strongly increasing trend thereafter. Policies and instruments are assessed in this light. Section 15.2 assesses the role of institutions and governance. Section 15.3 lays out the classification of policy instruments and packages, while 15.4 discusses the methodologies used to evaluate policies and institutions. The performance of various policy instruments and measures are individually assessed in Sections 15.5 and 15.6. The two main types of economic instruments are price instruments, that is, taxes and subsidies (including removal of subsidies on fossil fuels), and quantity instruments - emission-trading systems. These are assessed in Sections 15.5.2 and 15.5.3 respectively. An important feature of both these instruments is that they can be applied at a very broad, economy-wide scale. This is in contrast to the regulation and information policies and voluntary agreements which are usually sector- specific. These policies are assessed in Sections 15.5.4, 15.5.5, and 15.5.7. Government provision and planning is discussed in 15.5.6. The next section, 15.6, provides a focused discussion on technology policy including research and development and the deployment and diffusion of clean energy technologies. In addition to technology policy, longer-term effects of the policies assessed in Section 15.5 are addressed in Section 15.6. Both these sections, 15.5 and 15.6, bring together lessons from policies and policy packages used at the sectoral level from Chapters 7 (Energy), 8 (Transport), 9 (Buildings), 10 (Industry), 11 (Agriculture, Forestry and Land Use) and Chapter 12 (Human Settlements, Infrastructure, and Spatial Planning). The following sections further assess the interaction among policy instruments, as they are not usually used in isolation, and the impacts of particular instruments depend on the entire package of policies and the institutional context. Section 15.7 reviews interactions, both beneficial and harmful, that may not have been planned. The presence of such interactions is in part a consequence of the multi-jurisdictional nature of climate governance as well as the use of multiple policy instruments within a jurisdiction. Section 15.8 examines the deliberate linkage of policies across national and sub-national jurisdictions. Other key issues are further discussed in dedicated sections. They are: the role of stakeholders including non-governmental organizations (NGOs) (15.9), capacity building (15.10), links between adaptation and mitigation policies (15.11), and investment and finance (15.12). Gaps in knowledge are collected in 15.13

The place of strategic environmental assessment in the privatised electricity industry

The private sector has given relatively little attention to the emergence of strategic environmental assessment (SEA); even recently privatised utilities, where SEA might be deemed particularly appropriate, and whose activities are likely to fall within the scope of the European Union SEA Directive, have shown less interest than might be expected. However, the global trend towards the privatisation of state-owned enterprises makes the adaptation of SEA towards these industries all the more pressing. This paper addresses the place that SEA might take within the electricity sector, taking the privatised UK electricity industry as an example. Particular challenges are posed by the radical restructuring of the industry, designed to introduce competitive behaviour, making the development of comprehensive SEA processes problematic, and requiring SEA to be placed in the context of corporate environmental policy and objectives.</p

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHK alpha). due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [F-18]fluoromethyl-[1,2-H-2(4)]choline ([F-18]D4-FCH). [F-18]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a H-1/D-2 isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [F-18]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [F-18]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [F-18]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. the sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12–16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival