Cardio-oncology: concepts and practice

Substantial progress in cancer therapy increasingly allows higher cure rates, and even advanced disease can be stabilized, allowing improved survival with quality of life for months to years, meaning comorbid diseases are a growing determinant of outcome. Cardiovascular events substantially contribute to long-term morbidity and mortality in people living with or surviving cancer. In recognition of this, the subspecialty of cardio-oncology has emerged, and aims to promote cardiovascular heath, whilst facilitating the most effective cancer therapy. This review describes the concept of cardio-oncology, and illustrates the role played by a specialist team in improving outcomes, using heart failure secondary to breast cancer treatment as an example. We aim to highlight pivotal original research and comprehensive summaries of the most relevant topics, providing an overview for cardiologists and oncologists about this increasingly important medical problem

Metabolomic systems biology of trypanosomes

Metabolomics analysis, which aims at the systematic identification and quantification of all metabolites in biological systems, is emerging as a powerful new tool to identify biomarkers of disease, report on cellular responses to environmental perturbation, and to identify the targets of drugs. Here we discuss recent developments in metabolomic analysis, from the perspective of trypanosome research, highlighting remaining challenges and the most promising areas for future research

Investigating a human DNA repair helicase that supports CRISPR editing

In the last decade, CRISPR-associated proteins such as Cas9 and Cas12a have become powerful gene-editing tools for research, with great potential for therapeutic applications. However, barriers remain to their successful implementation, one of which is understanding the interaction of these systems with DNA repair processes. Previous research has identified HelQ, an ATP-dependent single-stranded DNA helicase implicated in replication-coupled repair, as a major factor in the efficient integration of template DNA through homology-directed pathways. HelQ has also been identified as a prognostic biomarker for several different cancers and a promising target in platinum-resistant ovarian tumours. We hypothesised that HelQ removes Cas-proteins from the sites of double-strand breaks, but in vitro assays utilising both synthetic DNA substrates and supercoiled plasmid DNA were unable to confirm this. Alongside this, a system of human-derived cell-free extracts was reconstituted to study the impact of individual DNA repair proteins on integration efficiency. Further exploration into the role of HelQ in the resolution of DNA:RNA hybrids was also undertaken, ultimately finding conflicting evidence for the participation of the protein. Previous research has demonstrated sensitisation to DNA-crosslinking agents in HelQ-deficient cells. To further characterise the importance of this, research was conducted using HelQ-depleted cell lines. This generated preliminary data laying the groundwork for a future functional genomic screen against HelQ. Finally, using fragment-based drug discovery techniques, a small molecule screen identified putative inhibitors against HelQ in vitro. Subsequent testing to validate and characterise hits identifying several candidates with micromolar IC50 values. Experiments to determine the mode-of-action suggest that many compounds were competitive with ATP, although several candidates were identified which may disrupt HelQ DNA binding or helicase activities

LC-MS for the metabonomic study of human urine samples

The field of metabonomics is beginning to grow rapidly due to the ability to analyse biofluids, providing a 'snapshot' of biological processes that have happened (cf: proteomic/transcriptomic studies, which predict what may happen), making it possible to profile responses over time. The work described in this thesis was motivated by the aim of profiling clinical urine samples obtained from fracture patients, with a view to identifying potential biomarkers related to failed fracture healing. This led to the need to develop and evaluate metabonomic approaches, specifically a orthogonal separation approach complementary to the commonly-used reversed phase (RP) separation methods, namely hydrophilic interaction liquid chromatography (HILI C). Urine samples from healthy volunteers were collected and used to develop an LCMS 'metabonomic toolbox'. This development evaluated various aspects of a· metabonomic study that are commonly poorly reported within the literature: 'study design, sample collection storage and handling considerations, data extraction, normalisation and scaling methods, and multivariate data analysis tools. From the literature, the commonly-used method of normalising to creatinine was ' found to be unsuitable due to perturbations in the urinary excretion of creatinine due to factors such as illness. Methods used to evaluate system ~tability were also developed and added to the 'toolbox'. HILIC was successfully used as a separation technique orthogonal to RP, producing comparable results but using different metabolites; this highlights the fact that much potential information is P?ssibly being lost when only RP-LC-MS methods are used for analysis.The need to use both modes of ionisation polarity were also addressed for an increased coverage in biofluid metabolite profiles. , The knowledge gained in the development of the 'metabonomic toolbox' was used for the analysis of clinical urine samples. Despite the lack of properly time-setted samples and none of the recruited patients suffering delayed fracture healing, potential metabolites related to fracture healing were found. However, the samples were very different to previously-analysed samples from healthy volunteers; they , showed very large amounts of protein, which had a large range of molecular weights. These were' identified- proteomically. Finally, ESI-Q-o-ToF MS/MS, MALDI-ToFlToF MS/MS and racemic amino acid analysis were used for the structural determination of a pseudomonad biosurfactant, which was identified, unexpectedly, as the cyclic Iipopeptide white line inducing principle, WLIP

Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men

This article is available open access through the publisher’s website. Copyright @ 2010 American Heart Foundation.Objective— Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. Methods and Results— In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor l-NMMA, and norepinephrine.  Flow-mediated vasodilatation (5.8%±0.4% vs 7.9%±0.5%; P=0.002) and CPC mobilization (CD34+/KDR+ 53.2% vs 85.4%; P=0.001; CD133+/CD34+/KDR+ 48.4% vs 73.9%; P=0.05; and CD34+/CD45− 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34+/KDR+ −3.3% vs 68.4%; CD133+/CD34+/KDR+ 0.7% vs 71.4%; and CD34+/CD45− −30.5% vs 77.8%; all P<0.001). Conclusion— In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.British Heart Foundatio

Case registers for mentally handicapped people.

This thesis is an evaluation of mental handicap registers as planning tools and is based on a national postal survey and semi-structured interviews with register-operators. Registers have emerged from pressure for greater rationality in planning the health and social services, a co-ordinated approach to priority groups, and a radical change in attitude to mental handicap. Mental handicap registers are found to be organisationally, financially and morally feasible. Moreover they can develop naturally as by-products of Community Mental Handicap Teams, thereby significantly reducing the costs of data-collection. Registers provide a basis for service-planning which is more objective and takes account of more of the users of the service than the opinions of experienced professionals. Names, addresses, dates of birth and details of services used can make a considerable contribution to planning. In addition, some indicator of the services that subjects need is required. Register-operators tend to regard the widely-used Wessex Behaviour Rating System as a crude measure and hanker after a more direct assessment of need such as might be made at a multi-disciplinary review. Most registers hold identifying and service-details of their subjects; however there are a number of registers holding in addition a large amount of information for which there is little demand in planning. The data which registers have held have not been fully exploited partly because they have not been sufficiently closely linked to the planning process and the methods of planning have not been sufficiently receptive to quantitative data. Other statistical client-based data-bases for service-planning run the risk of similar neglect by decision-makers unless vigorous efforts are made to promote their use

Insulin Resistance Impairs Circulating Angiogenic Progenitor Cell Function and Delays Endothelial Regeneration

OBJECTIVE Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS IRKO mice, although glucose tolerant, had fewer circulating Sca-1+/Flk-1+ APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor–stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit+ bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals

CRISPR-Cas immunity, DNA repair and genome stability

© 2018 The Author(s). Co-opting of CRISPR-Cas ‘Interference’ reactions for editing the genomes of eukaryotic and prokaryotic cells has highlighted crucial support roles for DNA repair systems that strive to maintain genome stability. As front-runners in genome editing that targets DNA, the class 2 CRISPR-Cas enzymes Cas9 and Cas12a rely on repair of DNA double-strand breaks (DDSBs) by host DNA repair enzymes, using mechanisms that vary in how well they are understood. Data are emerging about the identities of DNA repair enzymes that support genome editing in human cells. At the same time, it is becoming apparent that CRISPR-Cas systems functioning in their native environment, bacteria or archaea, also need DNA repair enzymes. In this short review, we survey how DNA repair and CRISPR-Cas systems are intertwined. We consider how understanding DNA repair and CRISPR-Cas interference reactions in nature might help improve the efficacy of genome editing procedures that utilise homologous or analogous systems in human and other cells

Prioritizing symptom management in the treatment of chronic heart failure

Chronic heart failure (CHF) is a chronic, progressive disease that has detrimental consequences on a patient's quality of life (QoL). In part due to requirements for market access and licensing, the assessment of current and future treatments focuses on reducing mortality and hospitalizations. Few drugs are available principally for their symptomatic effect despite the fact that most patients' symptoms persist or worsen over time and an acceptance that the survival gains of modern therapies are mitigated by poorly controlled symptoms. Additional contributors to the failure to focus on symptoms could be the result of under‐reporting of symptoms by patients and carers and a reliance on insensitive symptomatic categories in which patients frequently remain despite additional therapies. Hence, formal symptom assessment tools, such as questionnaires, can be useful prompts to encourage more fidelity and reproducibility in the assessment of symptoms. This scoping review explores for the first time the assessment options and management of common symptoms in CHF with a focus on patient‐reported outcome tools. The integration of patient‐reported outcomes for symptom assessment into the routine of a CHF clinic could improve the monitoring of disease progression and QoL, especially following changes in treatment or intervention with a targeted symptom approach expected to improve QoL and patient outcomes

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study

Background Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. Methods and findings We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998–2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person–years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0–14.9 mg, 1.6% for 15.0–24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64–1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54–1.85) for atrial fibrillation, 1.75 (95% CI 1.56–1.97) for heart failure, 1.76 (95% CI 1.51–2.05) for acute myocardial infarction, 1.78 (95% CI 1.53–2.07) for peripheral arterial disease, 1.32 (95% CI 1.15–1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47–2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose–response estimates. Conclusions In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses