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  • Journal article
    Dobra R, Davies J, Elborn S, Kee F, Madge S, Boeri Met al., 2023,

    A discrete choice experiment to quantify the influence of trial features on the decision to participate in cystic fibrosis trials.

    , J Cyst Fibros

    BACKGROUND: Patient-centred trial design optimises recruitment and retention, reduces trial failure rates and increases the diversity of trial cohorts. This allows safe and effective treatments to reach clinic more quickly. To achieve this, patients' views must be incorporated into trial design. METHODS: A discrete choice experiment was used to quantify preferences of pwCF for trials features; medicine type, trial location, stipend, washout, drug access on trial completion and trial design. Respondents were presented pairs of hypothetical trial scenarios with different level combinations assigned through experimental design. Respondents were asked to pick their preferred option or decline both. The cross-sectional data were explored using a Random Parameters Logit model. RESULTS: We received 207 eligible responses between Oct2020-Jan2021. The strongest influence on the decision to participate was trial location; pwCF favour participation at their usual clinical centre. Greater travel distances made respondents less willing to participate. Post-trial drug access ranked second. pwCF would rather participate in modulator trials than trials of other drugs. In general, pwCF did not favour a washout period, but were more prepared to washout non-modulators than modulators. Stipend provision was not ranked highly, but higher stipends increased intention to participate. Trial design (placebo vs open-label) had minimal influence on the decision to participate. There are complex interactions between placebos and washouts. CONCLUSIONS: We used quantitative methods to systematically elicit preferences of pwCF for clinical trials' features. We explore the relevance of our findings to trial design and delivery in the current CF trials landscape.

  • Journal article
    Thee S, Ekkelenkamp M, Shah A, 2023,

    AMR-Lung: a European Clinical Research Collaboration on antimicrobial resistance in chronic lung disease.

    , Eur Respir J, Vol: 62
  • Journal article
    Beattie JW, Rowland-Jones RC, Farys M, Bettany H, Hilton D, Kazarian SG, Byrne Bet al., 2023,

    Application of Raman Spectroscopy to Dynamic Binding Capacity Analysis.

    , Appl Spectrosc, Vol: 77, Pages: 1393-1400

    Protein A affinity chromatography is a key step in isolation of biotherapeutics (BTs) containing fragment crystallizable regions, including monoclonal and bispecific antibodies. Dynamic binding capacity (DBC) analysis assesses how much BT will bind to a protein A column. DBC reduces with column usage, effectively reducing the amount of recovered product over time. Drug regulatory bodies mandate chromatography resin lifetime for BT isolation, through measurement of parameters including DBC, so this feature is carefully monitored in industrial purification pipelines. High-performance affinity chromatography (HPAC) is typically used to assess the concentration of BT, which when loaded to the column results in significant breakthrough of BT in the flowthrough. HPAC gives an accurate assessment of DBC and how this changes over time but only reports on protein concentration, requires calibration for each new BT analyzed, and can only be used offline. Here we utilized Raman spectroscopy and revealed that this approach is at least as effective as both HPAC and ultraviolet chromatogram methods at monitoring DBC of protein A resins. In addition to reporting on protein concentration, the chemical information in the Raman spectra provides information on aggregation status and protein structure, providing extra quality controls to industrial bioprocessing pipelines. In combination with partial least square (PLS) analysis, Raman spectroscopy can be used to determine the DBC of a BT without prior calibration. Here we performed Raman analysis offline in a 96-well plate format, however, it is feasible to perform this inline. This study demonstrates the power of Raman spectroscopy as a significantly improved approach to DBC monitoring in industrial pipelines.

  • Journal article
    Koudstaal T, Funke-Chambour M, Kreuter M, Molyneaux PL, Wijsenbeek MSet al., 2023,

    Pulmonary fibrosis: from pathogenesis to clinical decision-making.

    , Trends Mol Med, Vol: 29, Pages: 1076-1087

    Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.

  • Journal article
    Dobra R, Pinnell S, Jones A, Madge S, Simmonds NJ, Davies JCet al., 2023,

    How representative are clinical trial cohorts of the general CF population? Implications for trial planning.

    , J Cyst Fibros

    Understanding the number of patients eligible to participate in research is important to design protocols and define research priorities. We reviewed the records of all patients with CF, age 12+, who receive care at our centre. We assessed their eligibility for trial participation based on common trial inclusion/exclusion criteria. 643 patients were included in the analysis, 31 were modulator ineligible(MI). Only 198(31 %) of the total cohort and 7(23 %) of the MI cohort were eligible for participation based on the hypothetical criteria. The most common reason for ineligibility was ppFEV1 ≥90 % followed by clinical instability, complex comorbidity and anticipated inability to adhere to the protocol. We suggest this would be a useful exercise for centres planning to either participate in, or refer subjects into, upcoming trials to undertake for their own cohort. We also make suggestions for protocol designs that optimise the number of patients who are eligible to participate.

  • Journal article
    King F, Yuen ELH, Bozkurt TO, 2023,

    Border Control: Manipulation of the Host-Pathogen Interface by Perihaustorial Oomycete Effectors.

    , Mol Plant Microbe Interact, ISSN: 0894-0282

    Filamentous plant pathogens, including fungi and oomycetes, cause some of the most devastating plant diseases. These organisms serve as ideal models for understanding the intricate molecular interplay between plants and the invading pathogens. Filamentous pathogens secrete effector proteins via haustoria, specialised structures for infection and nutrient uptake, to suppress the plant immune response and to reprogram plant metabolism. Recent advances in cell biology have provided crucial insights into the biogenesis of the extrahaustorial membrane and the redirection of host endomembrane trafficking towards this interface. Functional studies have shown that an increasing number of oomycete effectors accumulate at the perihaustorial interface to subvert plant focal immune responses, with a particular convergence on targets involved in host endomembrane trafficking. In this review, we summarise the diverse mechanisms of perihaustorial effectors from oomycetes and pinpoint pressing questions regarding their role in manipulating host defense and metabolism at the haustorial interface.

  • Journal article
    Schindler D, Walker RSK, Jiang S, Brooks AN, Wang Y, Müller CA, Cockram C, Luo Y, García A, Schraivogel D, Mozziconacci J, Pena N, Assari M, Sánchez Olmos MDC, Zhao Y, Ballerini A, Blount BA, Cai J, Ogunlana L, Liu W, Jönsson K, Abramczyk D, Garcia-Ruiz E, Turowski TW, Swidah R, Ellis T, Pan T, Antequera F, Shen Y, Nieduszynski CA, Koszul R, Dai J, Steinmetz LM, Boeke JD, Cai Yet al., 2023,

    Design, construction, and functional characterization of a tRNA neochromosome in yeast.

    , Cell, Vol: 186, Pages: 5237-5253.e22

    Here, we report the design, construction, and characterization of a tRNA neochromosome, a designer chromosome that functions as an additional, de novo counterpart to the native complement of Saccharomyces cerevisiae. Intending to address one of the central design principles of the Sc2.0 project, the ∼190-kb tRNA neochromosome houses all 275 relocated nuclear tRNA genes. To maximize stability, the design incorporates orthogonal genetic elements from non-S. cerevisiae yeast species. Furthermore, the presence of 283 rox recombination sites enables an orthogonal tRNA SCRaMbLE system. Following construction in yeast, we obtained evidence of a potent selective force, manifesting as a spontaneous doubling in cell ploidy. Furthermore, tRNA sequencing, transcriptomics, proteomics, nucleosome mapping, replication profiling, FISH, and Hi-C were undertaken to investigate questions of tRNA neochromosome behavior and function. Its construction demonstrates the remarkable tractability of the yeast model and opens up opportunities to directly test hypotheses surrounding these essential non-coding RNAs.

  • Journal article
    Murphy RA, Pizzato J, Cuthbertson L, Sabnis A, Edwards A, Nolan L, Vorup-Jensen T, Larrouy-Maumus G, Davies Jet al., 2023,

    Antimicrobial peptide glatiramer acetate targets Pseudomonas aeruginosa lipopolysaccharides to breach membranes without altering lipopolysaccharide modification

    , Nature Portfolio Journals Antimicrobials and Resistance, ISSN: 2731-8745

    Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Both natural and synthetic AMPs are receiving renewed attention in the efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and are associated with increased morbidity and mortality. Cationic AMPs exploit the negative charge of lipopolysaccharides (LPS) on P. aeruginosa to bind to and disrupt the bacterial membrane(s) and cause lethal damage. P. aeruginosa modifies its LPS, via environmental or genetic factors, to neutralise the charge of the cell and evade AMP killing. Free-LPS is also a component of CF sputum, as is anionic extracellular DNA (eDNA), each of which can bind AMPs by electrostatic interaction. Both free LPS and eDNA also feed into pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer of glycine, lysine, alanine, and tyrosine and used as drug in the treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against P. aeruginosa from CF, functioning via bacterial membrane disruption. Here, we demonstrate direct binding and sequestration/neutralisation of P. aeruginosa LPS in keeping with GA’s ability to disrupt the outer membrane. Binding and neutralisation of eDNA was also seen. At CF-relevant concentrations, however, neither strongly inhibited membrane disruption by GA. Furthermore, in both type strains and clinical CF isolates of P. aeruginosa, exposure to GA did not result in increased modification of the Lipid A portion of LPS or in increased expression of genetically encoded systems involved in AMP sensing and LPS modification. With GA’s low selective pressure on P. aeruginosa for known AMP resistance mechanisms

  • Journal article
    Shaw WM, Khalil AS, Ellis T, 2023,

    A Multiplex MoClo Toolkit for Extensive and Flexible Engineering of Saccharomyces cerevisiae.

    , ACS Synth Biol, Vol: 12, Pages: 3393-3405

    Synthetic biology toolkits are one of the core foundations on which the field has been built, facilitating and accelerating efforts to reprogram cells and organisms for diverse biotechnological applications. The yeast Saccharomyces cerevisiae, an important model and industrial organism, has benefited from a wide range of toolkits. In particular, the MoClo Yeast Toolkit (YTK) enables the fast and straightforward construction of multigene plasmids from a library of highly characterized parts for programming new cellular behavior in a more predictable manner. While YTK has cultivated a strong parts ecosystem and excels in plasmid construction, it is limited in the extent and flexibility with which it can create new strains of yeast. Here, we describe a new and improved toolkit, the Multiplex Yeast Toolkit (MYT), that extends the capabilities of YTK and addresses strain engineering limitations. MYT provides a set of new integration vectors and selectable markers usable across common laboratory strains, as well as additional assembly cassettes to increase the number of transcriptional units in multigene constructs, CRISPR-Cas9 tools for highly efficient multiplexed vector integration, and three orthogonal and inducible promoter systems for conditional programming of gene expression. With these tools, we provide yeast synthetic biologists with a powerful platform to take their engineering ambitions to exciting new levels.

  • Journal article
    Pavlidou E, Papadopoulou SK, Tolia M, Mentzelou M, Tsoukalas N, Alexatou O, Tsiouda T, Tsourouflis G, Psara E, Bikos V, Kavantzas N, Kotta-Loizou I, Dakanalis A, Vorvolakos T, Giaginis Cet al., 2023,

    Association of Mediterranean diet adherence with disease progression characteristics, lifestyle factors and overall survival in gastric cancer patients.

    , Medical Sciences, Vol: 11, ISSN: 2076-3271

    BACKGROUND: The Mediterranean diet (MD) exerts a protective effect against cancer development and progression; however, the evaluation of its impact on gastric cancer still remains quite scarce. The present study aims to evaluate the association of MD adherence during the lifespan with disease progression characteristics, lifestyle factors and overall survival in gastric carcinoma patients. METHODS: This is an observational, cross-sectional study conducted on 186 gastric cancer patients followed up for a median time interval of 57 months or until death due to cancer disease. Tumor histopathological characteristics were retrieved from patients' medical records, while validated questionnaires assessing, immediately after the time of diagnosis, health-related quality of life, physical activity levels, sleep quality, depression, anxiety and MD adherence during the lifespan were used. RESULTS: Higher MD adherence during the lifespan was significantly associated with younger patients (p = 0.0106), regular smoking (p < 0.0001), abnormal BMI status (p < 0.0001), intestinal-type gastric carcinoma (p = 0.0111), high tumor histopathological grade (p < 0.0001) and earlier disease stage (p < 0.0001). Moreover, patients with elevated MD adherence during their lifespan showed significantly better health-related quality of life (p < 0.0001), higher physical activity levels (p < 0.0001), more adequate sleep quality (p < 0.0001) and lower prevalence of depression (p = 0.0003) and anxiety (p = 0.0006) compared to those with reduced MD adherence. In multiple regression analysis, elevated MD compliance during the lifespan was independently correlated with longer overall patient survival after adjustment for several confounders (Cox regression analysis, p = 0.0001). CONCLUSIONS: Higher MD adherence during the lifespan was associated with less advanced tumor histopathology characteristics and favorable mental and physical lifestyle factors. Moreover, higher MD adheren

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