Modulation of EGFR Activity by Molecularly Imprinted Polymer Nanoparticles Targeting Intracellular Epitopes

In recent years, molecularly imprinted polymer nanoparticles (nanoMIPs) have proven to be an attractive alternative to antibodies in diagnostic and therapeutic applications. However, several key questions remain: how suitable are intracellular epitopes as targets for nanoMIP binding? And to what extent can protein function be modulated via targeting specific epitopes? To investigate this, three extracellular and three intracellular epitopes of epidermal growth factor receptor (EGFR) were used as templates for the synthesis of nanoMIPs which were then used to treat cancer cells with different expression levels of EGFR. It was observed that nanoMIPs imprinted with epitopes from the intracellular kinase domain and the extracellular ligand binding domain of EGFR caused cells to form large foci of EGFR sequestered away from the cell surface, caused a reduction in autophosphorylation, and demonstrated effects on cell viability. Collectively, this suggests that intracellular domain-targeting nanoMIPs can be a potential new tool for cancer therapy

Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase IIa trial.

Background: Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anti-cancer properties. Objective: This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared to FOLFOX + 2 g daily oral curcumin (CUFOX). Methods: Twenty eight patients aged >18 with a histological diagnosis of metastatic colorectal cancer were randomized (1:2) to receive either FOLFOX or CUFOX. Safety was assessed by Common Toxicity Criteria-Adverse Event (CTC-AE) reporting, and efficacy via progression free survival (PFS) and overall survival (OS). Quality of life and neurotoxicity were assessed using questionnaires (European Organization for Research and Treatment Quality of life (EORTC QLQ-C30) and Functional Assessment of Cancer Treatment-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX)). Plasma curcuminoids were determined with liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS/MS) and CXCL1 by enzyme-linked immunosorbent assay (ELISA). Results: Addition of daily oral curcumin to FOLFOX chemotherapy was safe and tolerable (primary outcome). Similar adverse event profiles were observed for both arms. In the intention to treat population, the hazard ratio for PFS was 0.57 (0.24, 1.36) (P = 0.2) (median of 171 vs 291 days for FOLFOX and CUFOX respectively), and for OS was 0.34 (0.14, 0.82) (P = 0.02) (median of 200 vs 502 days for FOLFOX and CUFOX respectively). There was no significant difference between arms for quality of life (P = 0.248) or neurotoxicity (P = 0.223). Curcumin glucuronide was detectable at levels >1.00 pmol/mL in 15 of 18 patients receiving CUFOX. Curcumin did not significantly alter CXCL1 over time (P = 0.712). Conclusions: Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer. Trial registration was with ClinicalTrials.gov (NCT01490996) and the European Drug Regulating Authorities (EudraCT 2011-002289-19)

Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study.

BACKGROUND: Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. METHODS: We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. RESULTS: The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. CONCLUSIONS: Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. TRIAL REGISTRATION NUMBER: Results, NCT01620645

Atrial fibrillation in UK South Asian hospitalized ischemic stroke patients: the BRAINS study

Introduction South Asian diaspora comprise one of the largest ethnic minority groups in the world yet data about atrial fibrillation (AF) in this demographic is understudied. Our aim is to identify differences in AF prevalence and treatment between South Asians and white British stroke patients. Method The UK arm of a prospective ongoing large international repository on stroke was analysed. Ethnic differences in AF prevalence and management in those with ischemic stroke were analysed. Results Of the 3515 individuals recruited with ischemic stroke, 1482 (men: 972, women: 510) were South Asian and 2033 (men:1141, women:892) of white British ethnicity. AF was present in 462 white British and 193 South Asians stroke patients, with South Asians displaying a lower prevalence of AF (South Asians: 13.0% vs white British 22.7%, P<0.001). Despite adjustment for traditional AF risk factors, South Asians had a significantly lower OR of AF compared to white British stroke patients (OR: 0.40, 95%CI: 0.33:0.49, P<0.001). Among confirmed AF cases, 31.8% of South Asians and 41.4% of white British were untreated at admission (P = 0.02). Antiplatelet treatment was significantly higher among South Asians at both admission (South Asian: 47.4% vs. white British: 29.9%, P<0.001) and discharge (South Asian: 49.5% vs. white British: 34.7%, P = 0.001), although anticoagulation treatment was similar across both ethnic groups at admission (South Asian: 28.5% vs white British: 28.1%, P = 0.93), and discharge (South Asian: 45.1% vs white British: 43.1%, P = 0.64). Conclusion Stroke patients of South Asian descent are at significantly lower risk of AF but more likely to be on antiplatelet treatment compared to their white British counterparts