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Thermostable exoshells (tES) are engineered proteinaceous nanoparticles used for the rapid encapsulation of therapeutic proteins/enzymes, whereby the nanoplatform protects the payload from proteases and other denaturants. Given the significance of oral delivery as the preferred model for drug administration, we structurally improved the stability of tES through multiple inter-subunit disulfide linkages that were initially absent in the parent molecule. The disulfide-linked tES, as compared to tES, significantly stabilized the activity of encapsulated horseradish peroxidase (HRP) at acidic pH and against the primary human digestive enzymes, pepsin, and trypsin. Furthermore, the disulfide-linked tES (DS-tES) exhibited significant intestinal permeability as evaluated using Caco2 cells. In vivo bioluminescence assay showed that encapsulated Renilla luciferase (rluc) was ~3 times more stable in mice compared to the free enzyme. DS-tES collected mice feces had ~100 times more active enzyme in comparison to the control (free enzyme) after 24 h of oral administration, demonstrating strong intestinal stability. Taken together, the in vitro and in vivo results demonstrate the potential of DS-tES for intraluminal and systemic oral drug delivery applications.

Increasing MRI capacity is of primary importance to both NHS England and individual radiology departments. Consequently, central funding was provided to allow trusts to instal artificial intelligence-enabled image reconstruction (AI-IR) on their MRI scanners, with the stated aim of increasing capacity by two patients scanned per day within a year of installation on a given scanner. This work demonstrates how a two-phase quality improvement (QI) initiative can be followed to increase capacity using AI-IR in a community diagnostic centre (CDC) at Mile End Hospital and an acute trauma centre, the Royal London Hospital, in East London with comprehensive stakeholders’ engagement.The Model for Improvement framework was used. Our pilot study focused on 3 Plan-Do-Study-Act (PDSA) cycles for three anatomies in musculoskeletal (MSK) imaging at our CDC. A second, substantive study at our major trauma centre was followed, which was a 20-month project encompassing all MSK anatomies of interest.In our initial pilot study at the CDC, we were able to reduce booking times by 10 min for Knee, Ankle and Spine protocols. In our wide-ranging MSK programme at our trauma centre, we saved on average of 07:26 min per scan and while an increased throughput was not achieved, an increase in complex patients being scanned, from 7% to 15% was achieved, reducing healthcare inequities.Our two-centre study suggests that engaging with stakeholders in a structured QI programme can significantly reduce scanning times, improve patient experience and allow for longer precare and postcare time. Additionally, significant throughput increase at the CDC for low-risk ambulatory patients suggests efforts to increase capacity using this technology should be focused at such centres and other scanners focused on ambulatory outpatients, while for scanners focused on inpatients, paediatrics and A&E at trauma centres, the time saved can be used to increase the capacity for complex patients, reducing waiting times for these patients.

BackgroundDefects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.MethodsWe describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy.ResultsWe report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of β-DG.ConclusionsOur data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.

Background Gastric cancer, the fifth most prevalent cancer globally, poses significant treatment challenges due to factors such as late diagnosis, early metastasis, limited surgical options, and the systemic toxicity of chemotherapy. Because luminal barriers are often compromised in gastric cancers , orally administered therapies that enable localized absorption and drug release represent a promising new direction for site-specific treatment with limited side effects. Results We introduce a disulfide-linked thermostable exoshell system that orally delivers protein-based bioorthogonal catalytic centres directly to cancer tissues. The highly engineered exoshells effectively encapsulated and stabilized labile catalytic centres, preventing degradation in the harsh gastric environment. In vivo gastric tumors were treated using the anti-cancer properties of active metabolites of the prodrug indole-3-acetic acid (IAA) converted in situ via bioorthogonal catalysis. In vitro cell studies revealed a dose- and time-dependent inhibition of gastric cancer cell growth, irrespective of their HER2 status. This inhibition was accompanied by upregulation of mitochondrial lipid peroxidation, reduced mitochondrial membrane potential, and activation of necroptotic pathway markers such as RIP1, RIP3, and MLKL at both mRNA and protein levels. In a mouse model of gastric cancer induced by N-Methyl-N-Nitrosourea, oral administration of catalytic exoshells for 6 weeks significantly inhibited gastric inflammation and tumour polyp growth. Additionally, LC/MS/MS-based metabolomic analysis of plasma obtained from treated mice showed significant upregulation of cytotoxic metabolites of IAA. Notably, metabolites relevant to redox regulation, including alpha-tocopherol (vitamin E), glutathione (GSH), homocysteine, methyl cysteine, and cysteine sulfinic acid, were identified as the top differentially expressed metabolites, indicating potent suppression of inflammation and tumour growth. Histological analysis of gastric tissue showed a reduced number of polyps and subsequent development of gastric tumours. Conclusion Our in vitro and in vivo results demonstrated that exoshells possessed significant potential as an orally administered, titratable therapeutic platform for the management of gastrointestinal cancers. Graphical Abstract

Protein macromolecules occur naturally at the nanoscale. The use of a dedicated nanoparticle as a lyophilization excipient, however, has not been reported. Because biopolymeric and lipid nanoparticles often denature protein macromolecules and commonly lack the structural rigidity to survive the freeze-drying process, we hypothesized that surrounding an individual protein substrate with a nanoscale, thermostable exoshell (tES) would prevent aggregation and protect the substrate from denaturation during freezing, sublimation, and storage. We systematically investigated the properties of tES, including secondary structure and its homogeneity, throughout the process of lyophilization and found that tES have a near 100% recovery following aqueous reconstitution. We then tested the hypothesis that tES could encapsulate a model substrate, horseradish peroxidase (HRP), using charge complementation and pH-mediated controlled assembly. HRP were encapsulated within the 8 nm internal tES aqueous cavity using a simplified loading procedure. Time-course experiments demonstrated that unprotected HRP loses 95% of activity after 1 month of lyophilized storage. After encapsulation within tES nanoparticles, 70% of HRP activity was recovered, representing a 14-fold improvement and this effect was reproducible across a range of storage temperatures. To our knowledge, these results represent the first reported use of nanoparticle encapsulation to stabilize a functional macromolecule during lyophilization. Thermostable nanoencapsulation may be a useful method for the long-term storage of labile proteins.

Objective Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. Methods We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. Results We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. Conclusions Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Purpose The American College of Radiologists (ACR) recognises the value of magnetic resonance imaging (MRI) as the investigation of choice in patients with a clinically suspected scaphoid fracture but normal plain radiographs. The Royal College of Radiologists (RCR) in the UK produces no similar guidelines, as evidenced by the inconsistent management of such cases in hospitals around the UK. In discussion with our musculoskeletal radiologists, we implemented new guidelines to standardise management of our patients and now report our findings. Methods A consecutive series of 137 patients referred to the orthopaedic department with clinically suspected scaphoid fracture but normal series of plain radiographs were prospectively followed up over a two-year period. We implemented the use of early MRI for these patients and determined its incidence of detected scaphoid injury in addition to other occult injuries. We then prospectively examined results of these findings on patient management. Results Thirty-seven (27%) MRI examinations were normal with no evidence of a bony or soft-tissue injury. Soft-tissue injury was diagnosed in 59 patients (43.4%). Of those, 46 were triangular fibrocartilage complex (TFCC) tears (33.8%) and 18 were intercarpal ligament injuries (13.2 %). Bone marrow oedema with no distinct fracture was discovered in 55 cases (40.4%). In 17 (12.5%) cases, this involved only the scaphoid. In the remainder, it also involved the other carpal bones or distal radius. Fracture(s) were diagnosed on 30 examinations (22.0%). Conclusions MRI should be regarded as the gold standard investigation for patients in whom a scaphoid fracture is suspected clinically. It allows the diagnosis of occult bony and soft-tissue injuries that can present clinically as a scaphoid fracture; it also helps exclude patients with no fracture. We believe that there is a need to implement national guidelines for managing occult scaphoid fractures.

Myelodysplastic syndromes (MDS) are due to defective hematopoiesis in bone marrow characterized by cytopenia and dysplasia of blood cells, with a varying degree of risk of acute myeloid leukemia (AML). Currently, the only potentially curative strategy is hematopoietic stem cell transplantation (HSCT). Many patients are ineligible for HSCT, due to late diagnosis, presence of co-morbidities, old age and complications likely due to graft-versus-host disease (GvHD). As a consequence, patients with MDS are often treated conservatively with blood transfusions, chemotherapy, immunotherapy etc. based on the grade and manifestations of MDS. The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized immunotherapy for hematological malignancies, as evidenced by a large body of literature. However, resistance and toxicity associated with it are also a challenge. Hence, there is an urgent need to develop new strategies for immunological and hematopoetic management of MDS. Herein, we discuss current limitations of CAR T-cell therapy and summarize novel approaches to mitigate this. Further, we discuss the in vivo activation of tumor-specific T cells, immune check inhibitors (ICI) and other approaches to normalize the bone marrow milieu for the management of MDS.

Background Osteoarthritis is the prevailing form of inflammatory condition in joints of adults and the aging population, leading to long-term disability and chronic pain. Current therapeutic options have variable therapeutic efficacy and/or several side effects. Methods A randomized, placebo-controlled, double-blind clinical trial was conducted in 62 participants using a nutraceutical [standardized Boswellia serrata Roxb. gum resin (300 mg) and Apium graveolens L. seed extract (250 mg)], to determine its safety and efficacy for supporting cartilage health and reduction in knee osteoarthritis symptoms. All participants were assessed for physical function and pain with the help of WOMAC, VAS, Physicians' Global Assessment for the six-minute walk test/pain. Knee X-ray, KOOS questionnaire score, and FACIT-F score were assessed. Additionally, inflammatory, cartilage degeneration and regeneration biomarkers in serum and urine were evaluated at baseline and after 90 days of treatment. Results Oral administration of the nutraceutical resulted in prolonged symptomatic relief with reduced pain, stiffness, and swelling. Inflammatory (serum IL-7, IL-1, IL-6, hs-CRP, TNF-α, ESR) and cartilage degeneration biomarkers (serum CTX-II, COMP, MMP-3 and urinary CTX-II) were decreased in the nutraceutical group compared to baseline and placebo. Furthermore, serum N-propeptide of collagen IIA (PIIANP) and procollagen-type-C propeptide (PIICP) levels were increased in the nutraceutical group, suggesting collagen synthesis contributing to cartilage regeneration. At given doses for 90 days, there were no adverse effects based on the clinical examination, biochemical, hematological, and ECG analysis. Conclusions Taken together, the combination of Boswellia and celery could be a safe and promising herbal nutraceutical option for managing osteoarthritis and cartilage health effectively.