Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.

Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses.

Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation.

Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time.

Odorants from the Thermal Treatment of Hydrolyzed Mushroom Protein and Cysteine Enhance Saltiness Perception.

Innovative approaches to develop flavors with high sensory appeal are critical in encouraging increased consumer preference and adoption of low sodium foods. Gas chromatography-olfactometry, coupled with stable isotope dilution assays and sensory experiments, led to the identification of the odorants responsible for an enhancement in saltiness perception of chicken broth prepared with thermally treated enzymatically hydrolyzed mushroom protein and cysteine, then reacted under kitchen-like cooking conditions. Comparative aroma extract dilution analysis revealed 36 odorants with flavor dilution factors between a range of 1 and 256.

Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency.

Doxorubicin is a chemotherapeutic agent that is commonly used to treat a broad range of cancers. However, significant cardiotoxicity, associated with prolonged exposure to doxorubicin, limits its continued therapeutic use. One strategy to prevent the uptake of doxorubicin into cardiac cells is the encapsulation of the drug to prevent non-specific uptake and also to improve the drugs' pharmacokinetic properties.

Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment.

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule.

High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles.

Exosomes are extracellular vesicles that mediate cell-to-cell communication by transferring biological cargo, such as DNA, RNA and proteins. Through genetic engineering of exosome-producing cells or manipulation of purified exosomes, it is possible to load exosomes with therapeutic molecules and target them to specific cells via the display of targeting moieties on their surface. This provides an opportunity to exploit a naturally-occurring biological process for therapeutic purposes.

Mono-syllabic word test score as a pre-operative assessment criterion for cochlear implant candidature in adults with acquired hearing loss.

Rationale: Cochlear Implant (CI) candidates with a ski-slope hearing loss may be outside current implantation criteria [< 50% on Bamford-Kowal-Bench (BKB) sentence testing], despite having a significant hearing disability and limited benefit from conventional amplification.

Aim: To use existing post-operative performance data to establish a criterion for Arthur Boothroyd (AB) word test for CI candidacy assessment.

Methodology: Retrospective analysis of post-operative AB words scores for 64 CI users was performed and the 10th percentile score selected as a criterion of reasonable chance for post-operative improvement.

Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.

To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.

Development of a high-throughput human rhinovirus infectivity cell-based assay for identifying antiviral compounds.

Asthma and chronic obstructive pulmonary disease exacerbations are associated with human rhinovirus (HRV) lung infections for which there are no current effective antiviral therapies. To date, HRV infectivity of cells in vitro has been measured by a variety of biochemical and immunological methods. This paper describes the development of a high-throughput HRV infectivity assay using HeLa OHIO cells and a chemiluminescent-based ATP cell viability system, CellTiter-Glo from Promega, to measure HRV-induced cytopathic effect (CPE).

Comparison of the history obtained by patient-completed questionnaires with doctors' standard notes for patients with acute abdominal pain.

Background: Studies have shown that proformas improve the information recorded by junior doctors when they clerk patients with acute abdominal pain. This increases their diagnostic accuracy, but doctors are reluctant to use them. Patient-completed questionnaires are being used in elective surgery, but can they be used for patients with acute abdominal pain?

Objective: To evaluate the history obtained by patient-completed questionnaires in patients with acute abdominal pain and compare this with the history recorded by the admitting junior doctors.

Cholecystectomy or Cholelithiasis - a Missed Marker for Hyperlipidaemia? A Combined Retrospective and Prospective Study.

Background: Multiple studies have shown an association between gallstones and abnormal lipids and the latter increases the risk of coronary artery disease and stroke. Our study investigates the current incidence of lipid abnormalities in patients who have undergone cholecystectomy (retrospective study) and who have gallstones (prospective study).

Methods: We conducted a retrospective analysis of the lipid profiles of 715 patients who underwent cholecystectomy in a rural district general hospital from 2003 to 2006.

Treatment of Helicobacter pylori in surgical practice: a randomised trial of triple versus quadruple therapy in a rural district general hospital.

Aim: To compare a lansoprazole-based triple versus quadruple therapy for Helicobacter pylori (H pylori) eradication with emphasis on side effect profile, patient compliance and eradication rate at a rural district general hospital in Wales, United Kingdom.

Methods: One hundred one patients with H pylori infection were included in the study. Patients were randomised to receive triple therapy comprising of lansoprazole 30 mg, amoxycillin 1 g, clarithromycin 500 mg, all b.

Quantitation of urinary glycosaminoglycans using dimethylene blue as a screening technique for the diagnosis of mucopolysaccharidoses: an evaluation.

Background: The mucopolysaccharidoses (MPSs) are a group of inherited disorders due to defects in lysosomal enzymes catalysing the breakdown of glycosaminoglycans (GAGs). Usually they are detected using techniques to separate the accumulating GAGs in urine. However more recently an improved dye-based method measuring total urine GAG concentrations has become available.

Should doctors stop taking the generic history? A comparison of house officers' and nursing staff clerking in general surgery.

Purpose: The purpose of this paper is to show how the implementation of the European Working Time Directive in August 2004 has dramatically decreased junior doctors' working hours, as a consequence of which new ways of working will need to be found. Traditionally both doctors and nurses record the same generic history (past medical history, social and family history, drug history and allergies) in their own notes. This is unnecessary duplication and maybe only nursing staff should record this information.

Tyrosinemia type I--diagnostic issues and prenatal diagnosis.

A fifteen-month-old boy, born to consanguineously married couple, presented with asymptomatic hepatomegaly. Investigations revealed mildly deranged liver functions, necroinflammatory changes and cirrhosis on liver biopsy, a markedly raised alpha feto protein and tyrosine levels in plasma and a generalized aminoaciduria. His diagnosis of hereditary tyrosinemia was established on findings of raised serum and urine succinylacetone and a deficient activity of fumaryl acetoacetate hydroxylase enzyme.

Who should stage upper gastrointestinal tract malignancy?

District general hospitals with trained upper gastrointestinal surgeons should undertake staging of patients with upper gastrointestinal cancers within their catchment areas. This could considerable reduce the workload at regional cancer centres.

Structure-function studies of the C3a-receptor: C-terminal serine and threonine residues which influence receptor internalization and signaling.

The anaphylatoxic peptide C3a is a pro-inflammatory mediator generated during complement activation, whose specific G protein coupled receptor is expressed on granulocytes, monocytes, mast cells, activated lymphocytes, and in the nervous tissue. We have generated RBL-2H3 cell clones stably expressing mutants of the human C3a-receptor (C3aR) with combined alanine (Ala) substitutions of ten C-terminal serine (Ser) or threonine (Thr) residues, which may represent putative phosphorylation sites to characterize their role in ligand-induced C3aR internalization and signaling. Ser475/479 and Thr480/481 as well as Ser449 seemed not to be involved in ligand-induced receptor internalization.

Helicobacter pylori prevents proliferative stage of angiogenesis in vitro: role of cytokines.

Inhibition of angiogenesis may explain the delayed ulcer healing following Helicobacter pylori infection. We have previously demonstrated that H. pylori can inhibit endothelial cell proliferation.

Sequence-specific recognition of collagen triple helices by the collagen-specific molecular chaperone HSP47.

HSP47 is a molecular chaperone that plays an unknown role during the assembly and transport of procollagen. Our previous studies showed that, unlike most chaperones, HSP47 interacts with a correctly folded substrate. We suggested that HSP47 either stabilizes the correctly folded collagen helix from heat denaturation or prevents lateral aggregation prior to its transport from the endoplasmic reticulum.