Synthesis and applications of protein/peptide-polymer conjugates

Recent advances in synthetic methodologies have brought us closer than ever to the precision conferred by nature. For example, the control possible in reversible deactivation radical polymerization enables us to design and synthesize macromolecules with unprecedented control over not only the polymer chain ends, but also the side chain functionality. Furthermore, this functionality can be exploited to afford chemical modification of peptides and proteins, with ever-improving site-specificity, yielding a range of well-defined protein/peptide-hybrid materials. Such materials benefit from the amalgamation of the properties of proteins/peptides with those of the synthetic (macro)molecules in question. Here, the latest developments in the synthesis of functional polymers and their use for preparation of well-defined protein/peptide-polymer conjugates will be discussed, with particular attention focused on modulating the stability, efficacy and/or administration of therapeutic peptides

A review of the benefits and drawbacks to virtual field guides in today’s Geoscience higher education environment

Virtual Field Guides are a way for educators to tackle the growing issue of funding pressures in areas of higher education, such as geography. Virtual Field Guides are however underutilised and can offer students a different way of learning. Virtual Field Guides have many benefits to students, such as being more inclusive, building student skills and confidence in a controlled environment pre fieldtrip and can increase engagement in the topic studied. There are also benefits to the educator, such as reduced cost, more efficient students on fieldwork tasks and the ability to tailor and update their field guides to suit their needs. However there are drawbacks in the challenge of creation and their outcome as educational standalone tools. This paper reviews the literature around the benefits and draw backs to the creation and incorporation of virtual field guides in geoscience education. © 2017, The Author(s)

Strain‐Promoted Cycloadditions in Lipid Bilayers Triggered by Liposome Fusion

Due to the variety of roles served by the cell membrane, its composition and structure are complex, making it difficult to study. Bioorthogonal reactions, such as the strain promoted azide-alkyne cycloaddition (SPAAC), are powerful tools for exploring the function of biomolecules in their native environment but have been largely unexplored within the context of lipid bilayers. Here, we developed a new approach to study the SPAAC reaction in liposomal membranes using azide- and strained alkyne-functionalized Förster resonance energy transfer (FRET) dye pairs. This study represents the first characterization of the SPAAC reaction between diffusing molecules inside liposomal membranes. Potential applications of this work include in situ bioorthogonal labeling of membrane proteins, improved understanding of membrane dynamics and fluidity, and the generation of new probes for biosensing assays

Insight into ortho-boronoaldehyde conjugation via a FRET-based reporter assay

Ortho-boronoaldehydes react with amine-based nucleophiles with dramatically increased rates and product stabilities, relative to unfunctionalised benzaldehydes, leading to exciting applications across biological and material chemistry. We have developed a novel Förster resonance energy transfer (FRET)-based assay to provide key new insights into the reactivity of these boronoaldehydes, allowing us to track conjugation with unprecedented sensitivity and accuracy under standardised conditions. Our results highlight the key role played by reaction pH, buffer additives, and boronoaldehyde structure in controlling conjugation speed and stability, providing design criteria for further innovations and applications in the field

Photochemical Methods for Peptide Macrocylization

Photochemical reactions have been the subject of renewed interest over the last two decades, leading to the development of many new diverse and powerful chemical transformations. More recently, these developments have been expanded to enable the photochemical macrocylization of peptides and small proteins. These constructs benefit from increased stability, structural rigidity, and biological potency over their linear counterparts, providing opportunities for improved therapeutic agents. In this review, we provide an overview of both the established and emerging methods for photochemical peptide macrocyclization, highlighting both the limitations and opportunities for further innovation in the field

Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis

IMPORTANCE: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%. OBJECTIVE: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials. DATA SOURCES: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients. STUDY SELECTION: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded. MAIN OUTCOMES AND MEASURES: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis. RESULTS: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%). CONCLUSION AND RELEVANCE: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy

A systems approach to prion disease

Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrPSc replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches

Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial

Longitudinal realist evaluation of the dementia PersonAlised care team (D-PACT) intervention: protocol

BACKGROUND: Different dementia support roles exist but evidence is lacking on which aspects are best, for whom and in what circumstance, and on their associated costs and benefits. Phase 1 of the Dementia PersonAlised Care Team programme (D-PACT), developed a post-diagnostic primary care-based intervention for people with dementia and their carers and assessed the feasibility of a trial. AIM: Phase 2 of the programme aims to 1) refine our programme theory on how, when and for whom the intervention works and 2) evaluate its value and impact. DESIGN & SETTING: A realist longitudinal mixed-methods evaluation will be conducted in urban, rural, and coastal areas across Southwest and Northwest England where low-income groups or ethnic minorities (eg, South Asian) are represented. Design was informed by patient, public and professional stakeholder input and Phase one findings. METHOD: High volume qualitative and quantitative data will be collected longitudinally from people with dementia, carers and practitioners. Analyses will comprise: 1) realist longitudinal case studies; 2) conversation analysis of recorded interactions; 3) statistical analyses of outcome and experience questionnaires; 4 a) health economic analysis examining costs of delivery; 4b) realist economic analysis of high-cost events and 'near misses'. All findings will be synthesised using a joint display table, evidence appraisal tool, triangulation and stakeholder co-analysis. CONCLUSION: Our realist evaluation will describe how, why and for whom the intervention leads (or not) to change over time; it also demonstrates how a non-randomised design can be more appropriate for complex interventions with similar questions or populations

Epidemiologic Studies of Isoflavones & Mammographic Density

Isoflavones, phytoestrogens in soy beans with estrogen-like properties, have been examined for their cancer protective effects. Mammographic density is a strong predictor of breast cancer. This review summarizes studies that have examined the association between isoflavones and breast density. Observational investigations in Hawaii and Singapore suggest slightly lower breast density among women of Asian descent with regular soy intake, but two larger studies from Japan and Singapore did not observe a protective effect. The findings from seven randomized trials with primarily Caucasian women indicate that soy or isoflavones do not modify mammographic density. Soy foods and isoflavone supplements within a nutritional range do not appear to modify breast cancer risk as assessed by mammographic density