Rationale: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.Methods: This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomographyconfirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years.Measurement and Main Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P , 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P , 0.0001), FEV 1 % predicted (r = 20.33; P , 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P , 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P , 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV 1 decline (b coefficient, 20.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P , 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline.Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.

Artemisinin-based combination therapies have been crucial in driving down the global burden of malaria, the world’s largest parasitic killer. However, their efficacy is now threatened by the emergence of resistance in Southeast Asia and sub-Saharan Africa.

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

Prostate cancer (PCa) is the most commonly diagnosed malignancy in men. The current prevalent diagnosis method, prostate-specific antigen (PSA) screening test, has low sensitivity, specificity and is poor at predicting the grade of disease. Thus, new biomarkers are urgently needed to improve the PCa diagnosis and staging for the management of patients. The aim of this study is to investigate the first voided urinary sample after massage for biomarker discovery for PCa. In this work, untargeted metabolomic profiling of the first voided urinary sample after massage from 28 confirmed prostate cancer patients, 20 benign enlarged prostate patients and 6 healthy volunteers was performed using liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS). Single and multiple peptide protein and cross-linking molecules were identified using PEAKS software. Analytical and diagnostic performance was tested using the Student's t test, Benjamini Hochberg correction and the receiver operating characteristic (ROC) curves. Using differential display analysis to compare peptides and cross-linking molecules of urinary samples between patients with benign, enlarged prostate and malignant cancer, we identified multiple peptides derived from osteopontin (SPP1) and prothrombin (F2) that are lower in PCa patients than in benign and enlarged prostate. The diagnosis accuracies of SPP1 and F2 peptides are 0.65-0.77 and 0.68-0.72, respectively. In addition to this, there are significant differences between PCa and benign/enlarged prostate patients in pyridinoline (PYD) and deoxypyridinoline (DPD) (p value = 0.001). Differences also, as shown in the excretion of these molecules for different stages of PCa (p value = 0.04) as the level of DPD and DPD/PYD ratio, were high in patients with locally advanced tumours. The study underscores the importance of proteomics analysis, and our results demonstrate that a urinary-based in depth proteomic approach allows the potential identification of dysregulated pathways and diagnostic biomarkers.

BACKGROUND Fruit mousses are products with a relatively low amount of dietary fiber in a single portion, but with additional portions of soluble fiber they may be good alternative to fiber‐rich snacks as take‐away food. In the present study, the properties of new soluble dextrin fiber (SDexF) from potato starch were assessed to establish whether it could be used to enrich fruit mousses. The properties of SDexF that can affect processing and storage stability of enriched mousses were studied and compared with those of native potato starch and semiproducts (resulting from various drying temperatures). The effect of the addition of SDexF on the pasting properties of mousse was also analyzed. RESULTS The application of food‐grade hydrochloric and citric acids as catalysts in the dextrinization of food‐grade potato starch allowed to SDexF to be obtained. Despite the differences in characteristics of the semiproducts, the final SDexF preparations were very similar in the meaning of solubility, dextrose equivalent (DE), retrogradation, and pasting properties. SDexF preparations were characterized by a significantly lower retrogradation tendency, peak viscosity, final viscosity, and gelatinization enthalpy in comparison with both native starch and semiproducts. Soluble dextrin fiber was successfully added to banana‐apple mousse. The addition of SDexF to mousse did not cause any undesirable changes to the viscosity of the product, and surprisingly even resulted in mousse with lower viscosity. Turbidity and RVA studies revealed that SDexF was stable and retrogradation processes can be negligible during storage. CONCLUSION The SDexF obtained from potato starch can be a novel functional substance to increase the dietary fiber content of fruit or fruit and vegetable mousses. © 2020 Society of Chemical Industry

an allogeneic mixed-lymphocyte reaction (MLR). Lymphocyte proliferation (flow-cytometric measurement of CFSE) and cytokine production (multiplex bead array) were assessed at day 5. The proportion of lymphocytes primed to produce IFNg was measured at day 7 (intracellular staining). Results UPM-stimulation increased DC expression of the maturation marker CD83 (p = 0.0038) and chemokine receptor CCR7 (p = 0.0018). It had no effect on CD40 or MHC Class I expression. UPM-stimulation of DCs also significantly increased CD8 lymphocyte proliferation (p = 0.020), and the production of IFNg, TNFa and IL-13 by CD8 lymphocytes in MLR at day 5 (all p < 0.05; Table 1). The proportion of CD8 lymphocytes primed to produce IFNg was also increased by UPM-stimulation of DCs (p = 0.034). Conclusion No evidence of an impaired Tc1 response was seen with UPM-stimulated DCs, in contrast to our previous findings with CD4 T lymphocytes. This may be because CD8 lymphocytes are more primed to respond and produce cytokines at baseline. However, UPM-treatment of DCs did significantly increase DC expression of CCR7, which directs DCs to lymph nodes, and increased the priming of Tc1 and Tc2 responses in the absence of any other stimulation. Inhalation of UPM may give rise to pathological CD8 responses to otherwise innocuous novel antigens. Introduction Increasing evidence suggests accelerated ageing as a pathogenic mechanism in COPD. Methods and results Telomere length in circulating WBC, a marker of biological ageing, was assessed in 200 ex-smoker COPD patients (108 male, age 61.5 ± 6.4 years, FEV 1 45.6 ± 17.1% predicted), 50 ex-smokers with normal lung function (27 male, age 59.9 ± 7.3 years, FEV 1 109.1 ± 13.4%predicted) and 50 non-smoker healthy subjects (27 male, age 59.3 ± 8.3 years, FEV 1 113.2 ± 13.1% predicted). TL was assessed by qPCR and expressed as relative T/S ratio. S49 TELOMERE ATTRITION IN CIRCULATING WHITE BLOOD CELLS IN COPD RELATES TO LUNG FUNCTION AND OUTCOMESTL was shorter in COPD (0.77 ± 0.2 relative T/S ratio) than in both ex-smokers (0.83 ± 0.2 relative T/S ratio) and nonsmokers (0.84 ± 0.2 relative T/S ratio) (p < 0.05). Furthermore TL correlated negatively with age (r -0.17, p 0.007), emphysema score (r -0.217, p 0.001), number of exacerbations in the previous year to inclusion in the study (r -0.129, p 0.04), number of hospitalisations over 3 years follow-up (r -0.167, p 0.004) and positively with FEV 1 (r 0.135, p = 0.03) and arterial oxygen saturation (r 0.161, p 0.01). Conclusion COPD patients have evidence of premature ageing (shortened TL) compared to normal subjects irrespective of their smoking history. TL relates to FEV 1 , SatO 2 , exacerbation rate and hospitalisations.