Search results
Found 9878 matches for
Pleural fluid proteomics from patients with pleural infection shows signatures of diverse neutrophilic responses: The Oxford Pleural Infection Endotyping Study (TORPIDS-2)
Background Pleural infection is a complex disease with poor clinical outcomes and increasing incidence worldwide, yet its biological endotypes remain unknown. Methods We analysed 80 pleural fluid samples from the PILOT study, a prospective study on pleural infection, using unlabelled mass spectrometry. A total of 449 proteins were retained after filtering. Unsupervised hierarchical clustering and Uniform Manifold Approximation and Projection analyses were used to cluster samples and pathway analysis was performed to identify the biological processes. Protein signatures as identified by the pathway analysis were compared to microbiology as defined by 16S rRNA next-generation sequencing. Spearman and exact Fischer's methods were used for correlation assessment. Results Higher neutrophil degranulation was correlated with increased glycolysis (odds ratio (OR) 281, p<2.2×10−16) and pentose phosphate activation (OR 371.45, p<2.2×10−16). Samples dominated by Streptococcus pneumoniae exhibited higher neutrophil degranulation (OR 12.08, p=0.005), glycolysis (OR 11.4, p=0.006) and pentose phosphate activity (OR 12.82, p=0.004). Samples dominated by anaerobes and Gram-negative bacteria exhibited lower neutrophil degranulation (OR 0.15, p=0.01), glycolysis (OR 0.14, p=0.01) and pentose phosphate activity (OR 0.07, p=0.001). Increased activity of the liver and retinoid X receptors pathway was associated with lower risk of 1-year mortality (OR 0.24, p=0.04). Conclusions These findings suggest that pleural infection patients exhibit diverse responses of neutrophil-mediated immunity, glycolysis and pentose phosphate activation, which are associated with microbiology. Therapeutic targeting of the liver and retinoid X receptors pathway with agonists is a possible treatment approach.
Emerging strategies in the transplantation of HCV-infected pancreases to uninfected recipients: A narrative review.
The scarcity of suitable candidates for solid organ transplantation (SOT) represents a major barrier to the reduction of waiting lists. The introduction of direct-acting antiviral (DAA) therapeutics eliminates many of the risks associated with the transplantation of Hepatitis C Virus (HCV)-infected donor organs (D+) to uninfected recipients (R-) and may facilitate access to a substantial organ pool, previously considered unacceptably high risk. The extent of clinical investigation into the safety and feasibility of HCV D+/R- SOT varies between allograft types. Here, we review the current state of pancreatic HCV D+/R-transplant research. Studies are limited to small cohorts who received pancreas allografts from HCV-viraemic donors alongside a regimen of DAA therapy. As of 2025, seven studies investigated a total of 22 patients, using prophylactic or reactive treatment regimens. Outcomes have been positive, with universal viral eradication, favourable allograft function, and minimal HCV-related complications. A favourable adverse event profile is reported, mirroring studies in other transplanted organs. With the aim to increase clinical use of pancreatic HCV D+/R- SOT, further investigation in the field is necessary to validate these preliminary data. Larger studies are essential to evaluate long-term sequelae and optimise treatment protocols to subsequently establish a standard of care.
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity
AbstractCancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Local anaesthetic transperineal biopsy versus transrectal prostate biopsy in prostate cancer detection (TRANSLATE): a multicentre, randomised, controlled trial.
BackgroundProstate cancer diagnosis requires biopsy, traditionally performed under local anaesthetic with ultrasound guidance via a transrectal approach (TRUS). Local anaesthetic ultrasound-guided transperineal biopsy (LATP) is gaining popularity in this setting; however, there is uncertainty regarding prostate sampling, infection rates, tolerability, side-effects, and cost-effectiveness. TRANSLATE was a randomised clinical trial that aimed to compare detection of Gleason Grade Group (GGG) 2 or higher prostate cancer, side-effects, tolerability, and patient-reported outcomes, after LATP versus TRUS biopsy.MethodsIn this randomised clinical trial which was done at ten hospitals in the UK, patients aged 18 years or older were eligible if investigated for suspected prostate cancer based on elevated age-specific prostate-specific antigen or abnormal digital rectal examination, and if biopsy-naive having received pre-biopsy MRI on a 1·5 or higher Tesla scanner. Individuals were excluded if they had any previous prostate biopsy, extensive local disease easily detectable by any biopsy (prostate-specific antigen >50 ng/mL or entire gland replaced by tumour on MRI), symptoms of concurrent or recent urinary tract infection, history of immunocompromise, need for enhanced antibiotic prophylaxis, absent rectum, or inability to position in lithotomy. Participants were randomly assigned in a 1:1 ratio to receive LATP or TRUS biopsy, using web-based software with a randomisation sequence using a minimisation algorithm to ensure balanced allocation across biopsy groups for minimisation factors (recruitment site, and location of the MRI lesion). The primary outcome was detection of GGG 2 or higher prostate cancer, analysed in the modified intention-to-treat population (all randomly assigned to treatment who had a biopsy result available). Key secondary endpoints assessing post-biopsy adverse events were infection, bleeding, urinary and sexual function, tolerability, and patient-reported outcomes. This trial is registered with ClinicalTrials.gov (NCT05179694) and at ISRCTN (ISRCTN98159689), and is complete.FindingsBetween Dec 3, 2021, and Sept 26, 2023, 2078 (76%) of 2727 assessed individuals were eligible, and 1126 (41%) of 2727 agreed to participate. 1044 (93%) of the 1126 participants were White British. Participants were allocated to TRUS (n=564) or LATP (n=562) biopsy, and were followed up at time of biopsy, and at 7 days, 35 days, and 4 months post-biopsy. We found GGG 2 or higher prostate cancer in 329 (60%) of 547 participants with biopsy results randomly assigned to LATP compared with 294 (54%) of 540 participants with biopsy results randomly assigned to TRUS biopsy (odds ratio [OR] 1·32 [95% CI 1·03-1·70]; p=0·031). Infection requiring admission to hospital within 35 days post-biopsy occurred in 2 (<1%) of 562 participants in the LATP group compared with 9 (2%) of 564 in the TRUS group. No statistically significant difference was observed in the reporting of overall biopsy-related complications (LATP 454 [81%] of 562 vs TRUS 436 [77%] of 564, OR 1·23 [95% CI 0·93 to 1·65]), urinary retention requiring catheterisation (LATP 35 [6%] of 562 vs TRUS 27 [5%] of 564), urinary symptoms (median International Prostate Symptom Score: LATP 8 [IQR 4-14] vs TRUS 8 [4-13], OR 0·36 [95% CI -0·38 to 1·10]), nor sexual function (median International Index of Erectile Function score: LATP 5 [2-25] vs TRUS 8 [3-24], OR -0·60 [-1·79 to 0·58]) at 4 months after biopsy. Trial participants more commonly reported LATP biopsy to be immediately painful and embarrassing compared with TRUS (LATP 216 [38%] of 562 vs TRUS 153 [27%] of 564; OR 1·84 [95% CI 1·40 to 2·43]). Serious adverse events occurred in 14 (2%) of 562 participants in the LATP group and 25 (4%) of 564 in the TRUS group.InterpretationAmong biopsy-naive individuals being investigated for possible prostate cancer, biopsy with LATP led to greater detection of GGG 2 or higher disease compared with TRUS. These findings will help to inform patients, clinicians, clinical guidelines, and policy makers regarding the important trade-offs between LATP and TRUS prostate biopsy.FundingNational Institute for Health and Care Research (NIHR) Health Technology Assessment.
Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post‐radiotherapy, and those with de novo metastatic disease
AbstractBackgroundIt is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin‐fixed paraffin‐embedded (FFPE) prostate biopsies from cohorts with post‐radiotherapy (RT) long‐term clinical follow‐up has been limited. Utilizing parallel sequencing modalities, we performed a proof‐of‐principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with (i) stable PCa (sPCa) postprimary or salvage RT, (ii) progressing PCa (pPCa) post‐RT, and (iii) de novo metastatic PCa (mPCa).MethodsA cohort of 19 patients with diagnostic prostate biopsies (n = 6 sPCa, n = 5 pPCa, n = 8 mPCa) and mean 4 years 10 months follow‐up (diagnosed 2009–2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3′RNA sequencing (3′RNAseq) (n = 19), nanoString analysis (n = 12), and Illumina 850k methylation (n = 8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes and methylated genomic regions (MGRs).ResultsEighteen of 19 samples provided useable 3′RNAseq data. Principal component analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ~600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression‐free survival post‐RT (p < 0.0001) in an external cohort.Conclusions3′RNAseq, nanoString and 850k‐methylation analyses are each achievable from historical FFPE diagnostic pretreatment prostate biopsies, unlocking the potential to utilize large cohorts of historic clinical samples. Profiling similarities between individuals with pPCa and mPCa suggests biological similarities and historical radiological staging limitations, which warrant further investigation.
Age differences in immunity to human seasonal coronaviruses and the immunogenicity of ChAdOx1 nCoV-19 (AZD1222).
BackgroundChAdOx1 nCoV-19 (AZD1222) vaccine was widely deployed to protect against severe COVID-19 in adults, but the relationship between pre-existing immunity to human seasonal coronaviruses (HCoVs) and vaccine-induced SARS-CoV-2 (SCoV2) response across age groups remains unclear.MethodsWe analysed SCoV2 and HCoVs antibody profiles in UK volunteers (aged 6-≥70), assessing antibody levels, avidity, and FcγR binding after receiving one or two doses of ChAdOx1 nCoV-19. Adult cohorts from trials in Brazil and Kenya were also included to evaluate geographical impacts on baseline HCoVs and SCoV2 induced response.FindingsIn the UK cohort, younger individuals had higher SCoV2 IgG, avidity, FcγR binding and cross-reactivity, particularly towards OC43 and HKU1. The greatest differences were seen after the first dose of ChAdOx1 nCoV-19, but these effects diminished after the second dose. Although baseline HCoVs IgG varied geographically, similar trends were observed across adult cohorts with younger adults showing higher SCoV2 IgG compared to older adults (UK and Brazil).InterpretationThese findings contribute to a better understanding of the immunogenicity of ChAdOx1-based vaccines in various age groups. Determining whether this applies across other vaccines using same platform is essential for evaluating the viability of one-dose regimens in outbreak responses.FundingThe clinical trials COV002, COV003, COV004, and COV006 were made possible by funding from Astra Zeneca, the NIHR and the University of Oxford, UK Department of Health and Social Care, through the UK National Institute for Health and Care Research, the Wellcome Trust (220991), and Innovate UK (project 971614).
A new paradigm of islet adaptations in human pregnancy: insights from immunohistochemistry and proteomics
Abstract Physiological changes during pregnancy support foetal growth, including adaptations in pancreatic islets to maintain glucose homeostasis. We investigate these adaptations using rare, high-quality pancreatic tissue from pregnant human donors and matched controls. We profile islets from pregnant donors using proteomics and assess α- and β-cell characteristics, as well as prolactin receptor and serotonin 2B receptor expression. Proteomic profiling of microdissected human islets identifies 7546 proteins but shows minimal differences in protein expression. In pregnancy, we show that islet area increases 1.9-fold, α- and β-cell areas increase 4.3- and 1.9-fold, driven by an increase in cell number rather than hypertrophy. Prolactin receptor expression is higher in α but not β cells, and serotonin 2B receptor is undetectable in β cells. Glucagon-like peptide-1 abundance increases 2.9-fold in α cells. These findings indicate that the molecular mechanisms driving pregnancy-induced islet adaptations in humans differ from those in mice, highlighting the need for human-based studies.
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer's disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer's disease-relevant pathologies.
Immunogenicity and Safety of ChAdOx1 nCoV-19 (AZD1222) as a Homologous Fourth-Dose Booster: A Substudy of the Phase 3 COV003 Trial in Brazil
Objective: To address that, despite widespread use of ChAdOx1 nCoV-19 (AZD1222) as a COVID-2019 booster, fourth-dose clinical outcomes data are limited. We report immunogenicity and safety for ChAdOx1 nCoV-19 as a homologous fourth-dose booster. Participants and Methods: Participants (aged ≥18 years) who had received 2 doses of ChAdOx1 nCoV-19 in phase 3 COV003 trial in Brazil were offered a third dose after a planned dose interval from 11 to 13 months and a fourth dose after a planned interval from 6 to 15 months (both 5 × 1010 viral particles). All fourth doses were administered to substudy participants between August 18 and October 28, 2022. The data cutoff was December 9, 2022. The primary immunogenicity outcome was noninferiority of ancestral severe acute respiratory syndrome coronavirus (SARS-CoV)-2–neutralizing antibody responses 28 days after dose 4 versus dose 3. Solicited and unsolicited adverse events were recorded 7 and 28 days postdose 4, respectively. Results: 172 participants received a fourth dose (median interval postthird dose, 10.7 months). Ancestral SARS-CoV-2–neutralizing antibody titers postdose 4 were noninferior to those postdose 3; geometric mean fold rise was 1.9 (95% CI, 1.6-2.4; n=112). Immunogenicity results were consistent across all variants analyzed. Local and systemic solicited adverse events were reported in 60.3% (n=35/58) and 43.1% (n=25/58) of participants, respectively. Conclusion: Immune responses after a fourth dose of ChAdOx1 nCoV-19 were noninferior to those after a third dose across SARS-CoV-2 variants. The fourth dose was well tolerated with no emergent safety concerns, supporting the continued development of the ChAdOx1 platform in preparation for future pandemics. Trial Registration: clinicaltrials.gov Identifier: NCT04536051
Erythropoiesis in the human
Erythropoiesis is the production of haemoglobin-containing red blood cells for oxygen delivery to the tissues. Approximately 1-2 Ã- 1012red cells are produced each day, and this remarkable productivity under stable conditions is also complemented by the capacity for rapid and substantial expansion when required. This chapter describes the developmental origins of primitive and definitive erythropoiesis in the yolk sac, the fetal liver and the bone marrow. Our current understanding of the mechanisms of erythroid lineage specification from multipotent haemopoietic stem cells remains incomplete, but key erythroid-specific transcription factors are known to be critical in directing erythroid-specific transcription. Characteristic changes in morphology, gene expression and cell surface markers allow the identification of erythroid cells at different stages of their differentiation and maturation. At a system level, the hormone erythropoietin is the principal regulator of erythroid activity. Following upregulation of its transcription by Hypoxia-Inducible Factor, erythropoietin directs an expansion of the pool of erythroid precursors and accelerated red cell maturation. This, together with coordinated iron absorption and delivery, provides an appropriate response to hypoxia caused by reduced numbers of circulating red blood cells associated with a very wide spectrum of causes.
Evaluating Overton and Altmetric as tools for tracking healthcare research use and impact on policy and practice: a descriptive study
Background Since 2010, the UK’s National Institute for Health and Care Research has funded a policy research unit (PRU) focused on maternal and neonatal health, with a remit to build an evidence base for policy and clinical practice in this field. We explored the usefulness of the platforms Overton and Altmetric as tools to gain insight into the use of PRU research evidence in policy and practice. Methods We searched Overton and Altmetric using article DOIs to identify citations of PRU-funded articles in policy documents and clinical guidelines. We excluded citations of the research in lists of excluded evidence, academic journal articles, and unverifiable citations. To obtain a count of unique citing documents for each article, we merged multiple editions/versions, translations, and duplicates of the same document. We calculated latency from article publication date to citation date, and citation distribution over time. We also developed descriptive case studies to explore how the citing policy documents used highly-cited research evidence. Results The 110 published articles reporting research funded by the PRU received 134 unique policy document and clinical guideline citations; 43/110 articles (39%) were cited in at least one document. Most citing documents were authored by organisations based in the UK (52/134) and other high-income countries. Intergovernmental organisations accounted for around 15% of citations (20/134). The median time from article publication to citation was 183 weeks (range 0.4–575 weeks). Citation contexts varied; use of the evidence in citing documents included provision of general background information, detailed summaries of findings, and support/rationale for specific clinical recommendations. Conclusions Overton and Altmetric are useful tools for identifying and exploring the use of research evidence in healthcare policy and clinical guidance. However, citation analysis alone cannot provide the complete picture. The delay between evidence publication and use in policy warrants further investigation.
Developing the next-generation of adenoviral vector vaccines.
The COVID-19 pandemic saw the first extensive use of adenoviral vector vaccines, with over 3 billion doses produced during the first year of the pandemic alone and an estimated 6 million lives saved. These vaccines were safe and effective, and could be produced at low cost in several continents allowing widespread use in low- and middle-income countries (LMICs). Despite their successful deployment against SARS-CoV-2, their impact has been overshadowed by relatively lower immunogenicity in contrast to mRNA vaccine technologies and very rare but serious adverse events such as vaccine-induced thrombotic thrombocytopaenia (VITT). The next-generation of adenoviral vector vaccines must address these challenges: here, we explore strategies to improve immunogenicity and safety by novel serotype selection, vector engineering, capsid modification and new delivery technologies, and discuss opportunities for next-generation adenoviral vectors against infectious disease and cancer.
Selective remodelling of the adipose niche in obesity and weight loss.
Weight loss significantly improves metabolic and cardiovascular health in people with obesity1-3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.
Characteristics, outcomes, and maternity care experiences of women with children’s social care involvement who subsequently died: national cohort study and confidential enquiry
Objectives To investigate maternal mortality in the context of children's social care (CSC) involvement, and to explore the quality of maternity care that women with CSC involvement received. Design National cohort study and confidential enquiry. Setting MBRRACE-UK (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK) national surveillance dataset for deaths that occurred during pregnancy or up to a year after pregnancy, UK, 2014-22. Participants 1451 women who died during or in the year after pregnancy in the UK; 420 women (28.9%) had CSC involvement. 47 women's healthcare records were included in the confidential enquiry to describe the care of a random sample of women who died during the perinatal period who had CSC involvement. Main outcome measures Rates and causes of maternal deaths by CSC involvement and quality of care. Results A third (420/1451, 28.9%) of the women who died during or in the year after pregnancy had CSC involvement for their (unborn) baby. Women with CSC involvement were more likely to be aged ≤20 years (rate ratio 1.85, 95% confidence interval 1.27 to 2.63, compared with those aged 21-29 years), living in the most deprived areas (rate ratio 2.19, 1.42 to 3.50, compared with those least deprived), and less likely to be from black (rate ratio 0.56, 0.35 to 0.84) or Asian ethnic backgrounds (rate ratio 0.26, 0.14 to 0.44, compared with white women) than women who died with no known CSC involvement. Deaths occurred predominantly between six weeks and the year after pregnancy (75%), and higher proportions of deaths were caused by suicide, other psychiatric causes, including substance overdose, and homicide. A confidential enquiry identified that risk assessment and recognition, medication management, coordination of care, and staff competencies were essential components in providing personalised, holistic, and trauma-informed care when dealing with medical and social complexity. Multiple individual and systemic barriers hindered access and engagement with healthcare. Conclusions Women with CSC involvement who died during or in the year after pregnancy encountered multiple inequalities and were at an increased risk of maternal mortality from psychiatric causes and homicide. A critical review of current care pathways and policy changes is urgently needed to tailor care to the needs of this group of women and to look at the inequalities that disproportionately affect them.