Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

"I'm not being rude, I'd want somebody normal" Adolescents' perception of their peers with Tourette's syndrome; an exploratory study

Background: Tourette’s syndrome (TS) is a highly stigmatised condition, and typically developing adolescents’ motives and reason for excluding individuals with TS have not been examined. Aims: The aim of the study was to understand how TS is conceptualised by adolescents and explore how individuals with TS are perceived by their typically developing peers. Method: Free text writing and focus groups were used to elicit the views of twenty-two year ten students from a secondary school in South East England. Grounded theory was used to develop an analytical framework. Result: Participants’ understanding about the condition was construed from misconceptions, unfamiliarity and unanswered questions. Adolescents who conceived TS as a disorder beyond the individual’s control perceived their peers as being deprived of agency and strength and as straying from the boundaries of normalcy. People with TS were viewed as individuals deserving pity, and in need of support. Although participants maintained they had feelings of social politeness towards those with TS, they would avoid initiating meaningful social relationships with them due to fear of “social contamination”. Intergroup anxiety would also inhibit a close degree of social contact. Participants that viewed those with TS as responsible for their condition expressed a plenary desire for social distance. However, these behavioural intentions were not limited to adolescents that elicited inferences of responsibility to people with TS, indicating that attributional models of stigmatisation may be of secondary importance in the case of TS. Implications for interventions to improve school belonging among youths with TS are discussed

Intersection of inflammation and herbal medicine in the treatment of osteoarthritis

Herbal remedies and dietary supplements have become an important area of research and clinical practice in orthopaedics and rheumatology. Understanding the risks and benefits of using herbal medicines in the treatment of arthritis, rheumatic diseases, and musculoskeletal complaints is a key priority of physicians and their patients. This review discusses the latest advances in the use of herbal medicines for treating osteoarthritis (OA) by focusing on the most significant trends and developments. This paper sets the scene by providing a brief introduction to ethnopharmacology, Ayurvedic medicine, and nutrigenomics before discussing the scientific and mechanistic rationale for targeting inflammatory signalling pathways in OA by use of herbal medicines. Special attention is drawn to the conceptual and practical difficulties associated with translating data from in-vitro experiments to in-vivo studies. Issues relating to the low bioavailability of active ingredients in herbal medicines are discussed, as also is the need for large-scale, randomized clinical trial

Correction: Colloidal Cu/ZnO catalysts for the hydrogenation of carbon dioxide to methanol: investigating catalyst preparation and ligand effects

The production of methanol from CO2 hydrogenation is a promising potential route to a renewable liquid fuel and renewable energy vector. Herein, three distinct routes to make colloidal catalysts based on mixtures of Cu(0) and ZnO nanoparticles (NPs) and using low-temperature organometallic procedures are reported. The colloids are surface coordinatedy by a phosphinate ligand: Dioctylphosphinate ([DOPA]−), which delivers a high solubility in organic solvents. Further, the synthetic routes allow fine control of the ZnO:Cu and ligand loadings. The catalysts are prepared by mixing small NP (2 nm) of either Cu(0) or air-stable Cu2O NPs with ZnO NPs (3 nm), or by the synthesis of Cu(0) in presence of ZnO NPs (ZnO: 2 nm, Cu: 6 nm). The resulting colloidal catalysts are applied in the liquid phase hydrogenation of CO2 to methanol (210°C, 50 bar, 3:1 molar ratio of CO2:H2). The catalysts typically exhibit 3 times higher rates when compared to a heterogeneous Cu-ZnO-Al2O3 commercial catalyst (21 vs 7 mmolMeOH.gCuZnO-1.h-1). The characterisation of the post-catalysis colloids show clear Cu/ZnO interfaces (HR-TEM), which are formed under reducing conditions, as well as differences in the Cu(0) NP size (from 3 to 7 nm) and nanoscale restructuring of the catalysts. The combination of characterisation and catalytic results indicate that the activity is mostly dictated by the Cu(0) particle size and ligand loading. Smaller Cu(0) NPs exhibited lower turnover frequency (TOF) values, whereas higher ligand loadings ([DOPA]−:(Cu+Zn) of 0.2-1.1) lead to smaller Cu(0) NPs and reduce the formation of Cu/ZnO interfaces. UV-Vis spectroscopy reveals that the Cu(0) NPs are more stable to oxidation under air after catalysis than beforehand, potentially due to migration of ZnO onto the Cu surface whilst under catalytic conditions

Effects of two contrasting canopy manipulations on growth and water use of London plane (Platanus x acerifolia) trees

Aims: Two contrasting canopy manipulations were compared to unpruned controls on London plane trees, to determine the effects on canopy regrowth, soil and leaf water relations. Methods: ‘Canopy reduction’, was achieved by removing the outer 30 % length of all major branches and ‘canopy thinning’, by removing 30 % of lateral branches arising from major branches. Results: Total canopy leaf areas recovered within two and three years of pruning for the canopy-thinned and reduced trees respectively. Canopy reduction increased mean leaf size, nitrogen concentration, canopy leaf area density and conserved soil moisture for up to 3 years, whereas canopy thinning had no effects. Another experiment compared more severe canopy reduction to unpruned trees. This produced a similar growth response to the previous experiment, but soil moisture was conserved nearer to the trunk. Analysis of 13C and 18O signals along with leaf water relations and soil moisture data suggested that lower boundary layer conductance within the canopy-reduced trees restricted tree water use, whereas for the canopy-thinned trees the opposite occurred. Conclusions: Only canopy reduction conserved soil moisture and this was due to a combination of reduced total canopy leaf area and structural changes in canopy architecture

AI-based automation of enrollment criteria and endpoint assessment in clinical trials in liver diseases

\ua9 The Author(s) 2024.Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62–0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P &lt; 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses

Biomechanical effects of polyaxial pedicle screw fixation on the lumbosacral segments with an anterior interbody cage support

BACKGROUND: Lumbosacral fusion is a relatively common procedure that is used in the management of an unstable spine. The anterior interbody cage has been involved to enhance the stability of a pedicle screw construct used at the lumbosacral junction. Biomechanical differences between polyaxial and monoaxial pedicle screws linked with various rod contours were investigated to analyze the respective effects on overall construct stiffness, cage strain, rod strain, and contact ratios at the vertebra-cage junction. METHODS: A synthetic model composed of two ultrahigh molecular weight polyethylene blocks was used with four titanium pedicle screws (two in each block) and two rods fixation to build the spinal construct along with an anterior interbody cage support. For each pair of the construct fixed with polyaxial or monoaxial screws, the linked rods were set at four configurations to simulate 0°, 7°, 14°, and 21° lordosis on the sagittal plane, and a compressive load of 300 N was applied. Strain gauges were attached to the posterior surface of the cage and to the central area of the left connecting rod. Also, the contact area between the block and the cage was measured using prescale Fuji super low pressure film for compression, flexion, lateral bending and torsion tests. RESULTS: Our main findings in the experiments with an anterior interbody cage support are as follows: 1) large segmental lordosis can decrease the stiffness of monoaxial pedicle screws constructs; 2) polyaxial screws rather than monoaxial screws combined with the cage fixation provide higher compression and flexion stiffness in 21° segmental lordosis; 3) polyaxial screws enhance the contact surface of the cage in 21° segmental lordosis. CONCLUSION: Polyaxial screws system used in conjunction with anterior cage support yields higher contact ratio, compression and flexion stiffness of spinal constructs than monoaxial screws system does in the same model when the spinal segment is set at large lordotic angles. Polyaxial pedicle screw fixation performs nearly equal percentages of vertebra-cage contact among all constructs with different sagittal alignments, therefore enhances the stabilization effect of interbody cages in the lumbosacral area