Results
- Showing results for:
- Reset all filters
Search results
-
Journal articleCelsa C, Pressiani T, Nishida N, et al., 2026,
Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study
, JHEP Reports, Vol: 8, ISSN: 2589-5559Background & AimsDurvalumab plus tremelimumab (STRIDE) has emerged as a first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC). This international multicentre study aimed to evaluate the efficacy and tolerability of STRIDE or durvalumab monotherapy in routine clinical practice, comparing outcomes between patients within and outside key eligibility criteria for the HIMALAYA trial.MethodsFrom a database of 1,423 patients with advanced/unresectable HCC treated with immunotherapy across 35 centres, we analysed 233 patients receiving STRIDE or durvalumab monotherapy. Patients were categorized as HIMALAYA-IN or HIMALAYA-OUT based on key trial eligibility criteria (no prior systemic therapy, ECOG-PS 0–1, Child-Pugh class A, no Vp4 thrombosis). Baseline characteristics were assessed for overall survival (OS) and hepatic decompensation using a multivariable Cox model and competing-risk analysis, respectively. Objective response rates and treatment-related adverse events were recorded.ResultsOf the 233 patients, 123 (53%) were HIMALAYA-IN and 110 (47%) were HIMALAYA-OUT. STRIDE was given in 95% of HIMALAYA-IN patients. After median follow-up of 6.0 months, median OS was 20.4 months (95% CI 11.7-NR) in the overall population. HIMALAYA-IN patients achieved significantly longer OS than HIMALAYA-OUT patients (23.0 vs. 12.2 months; hazard ratio 0.61; 95% CI 0.39-0.96; p = 0.03). Macrovascular invasion and hepatic decompensation were independent negative prognostic factors in the whole cohort. Hepatic decompensation occurred in 10.5% of patients within 12 months from treatment start. Objective response rate was 23.7% and 17.8% of HIMALAYA-IN and -OUT patients, respectively. Patients achieving disease control (whole cohort: 59.4%) demonstrated 24-month OS of 58.2% in HIMALAYA-IN and 44.8% in HIMALAYA-OUT groups. Grade 3-4 treatment-related adverse events occurred in 16.3% of patients.ConclusionsSTRIDE shows reproducible effectiveness and an ac
-
Journal articleTsamouri L, Aljadeed N, Olona A, et al., 2026,
Distinct lipid transport proteins are regulated by innate immune stimuli
, Discovery Immunology, ISSN: 2754-2483Lipid transport plays a critical role in the distribution of lipids across subcellular compartments. This is pivotal during infection and other stress stimuli that increase metabolic demands. While lipid biosynthesis is regulated by immune stimuli, whether immune signalling also influences lipid transport mechanisms remains unexplored. Here, we demonstrate that TLR signalling impacts the gene expression of lipid transport proteins in human monocytic THP-1 cell line and compare it to the expression in primary bone marrow-derived mouse macrophages. Our data demonstrates that TLR4 signalling selectively modulates the expression of oxysterol binding protein-related proteins (ORPs), a key family of proteins that transport lipids between organelles. Remarkably, TLR4 activation led to the downregulation of several ORP family members in human THP1-derived macrophages. However, this response was less profound in mouse macrophages. In contrast, the expression of steroidogenic acute regulatory domain (STARD) proteins, many of which transport lipids between mitochondria and other compartments, exhibited no statistical difference. Moreover, IFNG, a cytokine that plays a key role in the immune response, did not considerably impact human ORP or STARD expression levels, either alone or in combination with LPS. Together, these results reveal that TLR signalling exerts selective and critical control over lipid trafficking pathways with important biological differences. These findings provide new insights into the crosstalk between immune signalling and lipid metabolism, which may offer novel targets to treat diseases characterized by dysregulated lipid pathways.
-
Journal articleLightstone L, 2026,
Preeclampsia and the Early Origins of Cardiorenal Disease.
, J Am Soc Nephrol, Vol: 37, Pages: 1379-1381 -
Journal articlePapargyris L, Chiu C, 2026,
Innate immune responsiveness predicts both enhanced cellular immunity and symptomatic disease after controlled human influenza infection
, Nature Medicine, ISSN: 1078-8956Controlled human influenza infection studies can uniquely interrogate the early immune factors associated with clinical outcome. Here, 27 healthy volunteers with low strain-specific serum neutralising antibody levels were challenged with influenza A/H3N2 virus. Twenty-two became infected, with 18 developing mild-moderate symptoms while 4 remained asymptomatic. Local and systemic immune profiling revealed innate pathways that engaged more rapidly and to a higher level in symptomatic individuals. Earlier monocyte and dendritic cell activation correlated with higher symptom scores but also enhanced natural killer (NK) and CD8+ T cell activation thereafter. At baseline, peripheral blood mononuclear cells (PBMCs) from symptomatics were more responsive to in vitro challenge, indicating a predisposition to divergent immunological outcomes at the time of virus exposure that was subsequently modulated by infection. These results show that human innate cell responsiveness is a predeterminant of both symptomatic disease and cellular immune responses known to promote viral clearance, suggesting potential targets for therapeutic intervention if decoupled.
-
Journal articleBhoori S, Rivoltini L, Pinato DJ, et al., 2026,
Efficacy of liver transplantation after response to atezolizumab-bevacizumab downstaging of intermediate and advanced hepatocellular carcinoma (ImmunoXXL).
, J Hepatol, Vol: 85, Pages: 117-129BACKGROUND & AIMS: Liver transplantation (LT) is a curative treatment option in early and intermediate hepatocellular carcinoma (HCC) following downstaging with locoregional therapies (LRT). Tumor response to immune checkpoint inhibitors may extend LT eligibility to intermediate and advanced stages. METHODS: In this prospective phase II study, patients with intermediate and advanced HCCs beyond extended transplant criteria, not amenable to further LRTs, were downstaged with atezolizumab-bevacizumab (Atezo-Bev) prior to LT. The primary endpoint was recurrence-free survival with safety and efficacy as additional outcomes. Spectral quantitative pathology and immune signatures in tumor tissue and peripheral blood were studied longitudinally. RESULTS: Sixteen patients with HCC beyond expanded transplant criteria (median tumor size 6.5 cm [IQR 3-8], median AFP 283 ng/ml [IQR 6-1,080], portal vein thrombosis 50%) were downstaged to LT after a median of 4.7 months (IQR 2.4-7.6). Prior LRTs were used in 15 (94%) patients. The washout period from the last Atezo-Bev dose to transplant was 57.5 (IQR 29-87) days. Median follow-up was 16 months (95% CI 4-22). Pre-transplant immune-related adverse events occurred in 3 (19%) patients and post-transplant acute rejection in 4 (25%). Post-LT 90-day morbidity and mortality were 62.5% (95% CI 35-85%) and 6.3% (95% CI 0.2-30%) respectively. Explant pathology revealed 10 complete and 6 partial responses. Responding patients harboured a tumor microenvironment with features suggestive of immune activation/extinguishment, correlated with duration of Atezo-Bev treatment and length of pre-LT washout. One (6.2%) HCC post-LT recurrence occurred during follow-up. Recurrence-free and post-transplant overall survival were 90% and 94% after 2 years, respectively. CONCLUSIONS: LT following Atezo-Bev downstaging achieves promising recurrence-free survival in intermediate and advanced HCC beyond conventional transplant criteria. Acute rejection see
-
Journal articleMarkiewicz PJ, Thompson G, Wardlaw JM, et al., 2026,
The Dementias Platform UK PET/MR harmonisation and test-retest study: assessment of PET repeatability and reproducibility across the national network.
, Eur J Nucl Med Mol Imaging, Vol: 53, Pages: 5110-5129PURPOSE: Positron emission tomography combined with magnetic resonance imaging (PET/MR) has not yet achieved the level of adoption of PET/CT. This study aimed to harmonise PET imaging protocols across a national PET/MR network and to quantitatively assess whether PET/MR can achieve reliability comparable to PET/CT. While previous PET test-retest studies have demonstrated good repeatability, they have typically been limited to small cohorts or restricted site configurations. METHODS: We conducted a multi-site harmonisation and rigorous test-retest study across the network of eight PET/MR scanners. Thirty-seven healthy older participants (65-90 years) underwent harmonised one-hour amyloid PET/MR scans using either [[Formula: see text]F]flutemetamol or [[Formula: see text]F]florbetaben on two occasions. Retest scans were performed under conditions of same-site repeatability or multi-site reproducibility. Harmonised acquisition and reconstruction protocols were applied, and amyloid burden was quantified on the Centiloid (CL) scale. RESULTS: CL values across 74 scans showed excellent test-retest agreement (ICC = 0.968), improving to 0.987 after exclusion of one attenuation correction related outlier. Mean test-retest variability was 2.58%. No statistically significant differences were observed across repeatability versus reproducibility conditions, scanner types, or tracers. CL measurements were highly consistent with three independent blinded visual reads. CONCLUSION: This study demonstrates that harmonised PET/MR achieves high reliability comparable to PET/CT. Although the accuracy of attenuation maps requires checks, this study supports the use of PET/MR for quantitative amyloid imaging in research and therapeutic trials, and provides a valuable open resource of image and raw PET/MR data for further methodological development.
-
Journal articleLiu Y, Pieters S, Bineva-Todd G, et al., 2026,
Iterative Bump-and-Hole Engineering Creates a Bioorthogonal Reporter for N-Acetylglucosaminyltransferase I.
, J Am Chem SocAsparagine-linked protein glycosylation is among the most frequent modifications of proteins trafficking through the secretory pathway. These glycans are manufactured in an assembly line process, yielding a common precursor that is then subjected to individual modifications with different levels of complexity. An important biosynthetic modulator is the incorporation of N-acetylglucosamine (GlcNAc) at distinct positions in N-linked glycan biosynthesis, commencing with the activity of the glycosyltransferase MGAT1. While mapping of N-glycans to their corresponding protein attachment sites is generally possible, not much is known about the glycoprotein substrate choice for MGAT1 and related transferases. Analogs of GlcNAc with small bioorthogonal tags can be incorporated into N-glycans. However, due to the promiscuity of some GlcNAc transferases, incorporation is of little specificity toward individual positions. Here, we report an iterative bump-and-hole approach for the design of a bioorthogonal precision tool to study the activity of MGAT1 in mammalian cells. Structure-informed protein engineering abrogated the activity of MGAT1 toward the nucleotide-sugar UDP-GlcNAc while retaining activity toward bumped, azide-modified analogs. Kinetic and computational analyses using a neural network approach informed the synthesis of a tailored UDP-GlcNAc analog with preferential acceptance by the engineered enzyme. Following substrate biosynthesis, the strategy allowed selective incorporation of a chemical tag on MGAT1 substrate proteins in living mammalian cells with little background incorporation by other GlcNAc transferases. Our work expands the toolbox for glycan-based reporter compounds.
-
Journal articleDabas R, Kabir L, Navaratnam N, et al., 2026,
PGC1α expression using targeted redox-responsive nanogels protects against prostate cancer in vivo.
, J Control ReleaseProstate cancer is among the most frequently diagnosed cancers in men in the UK and US. Increasing evidence implicates metabolic dysregulation as a critical driver of disease progression. Central to this process is peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) that promotes oxidative metabolism and mitochondrial biogenesis while inhibiting metastatic programs. This work investigated the therapeutic potential of PGC1α overexpression via mRNA delivery. Here, we report a prostate-specific, targeted disulphide-crosslinked nanogel system for intracellular delivery of mRNA encoding the N-terminal isoform of PGC1α (NT-PGC1α). Functionalization of the NGs with a peptide targeting prostate-specific membrane antigen (PSMA) enabled selective delivery of NT-PGC1α mRNA in PCa cells and 3D spheroid models. We confirmed sustained PGC1α expression, and increased mitochondrial protein content, indicative of enhanced mitochondrial biogenesis. These nanogels, which were prepared in situ using a nanopolymerization technique, exhibited high mRNA loading capacity, low cytotoxicity, and redox-responsive cargo release, enabling controlled cytosolic delivery following intracellular glutathione-mediated degradation. In vivo, systemic administration of the PSMA-targeted NT-PGC1α mRNA-loaded nanogels resulted in tumor-preferential accumulation and significant suppression of xenograft growth (by 73.4% relative to untreated control), with minimal systemic toxicity. This study presents the first example of a prostate-targeted, disulfide-crosslinked nanogel system for mRNA-mediated metabolic reprogramming in prostate cancer, and highlights its promise as a platform for future RNA-based targeted and precision stimuli-responsive cancer therapies.
-
Journal articleNuccio SP, Stasi M, Cadoni E, et al., 2026,
Function through shape: An overview of DNA G-quadruplexes in transcriptional regulation.
, Curr Opin Chem Biol, Vol: 93G-quadruplexes (G4s) are four-stranded nucleic acid structures formed by guanine-rich sequences. Over the past two decades, G4s have emerged as key elements in genome organisation and transcription. Their remarkable structural diversity distinguishes G4s from other non-canonical DNA structures, including i-motifs and triplexes. Recent evidence suggests that G4s may serve as emerging regulatory hubs for transcriptional control, adding complexity to simple models in which G4s act solely as recruiters of transcription factors at gene promoters. Emerging data indicate that G4s can influence nucleosome occupancy, chromatin accessibility, and long-range chromatin interactions. Recent evidence also suggests a key role of G4s in modulating the formation of biomolecular condensate, which have been widely implicated in the regulation of transcription and chromatin organisation. Altogether, these findings highlight the potential of G4s to act as architectural elements of chromatin. In this review, we examine what makes G4s structurally unique compared to other alternative DNA structures, and discuss their potential involvement in genome architecture, nucleosome occupancy, and chromatin looping. We also highlight recent methodological advances, from small molecule stabilisers to CRISPR-based precision targeting, that enabled the manipulation of individual G4s in their native genomic context, revealing context-dependent G4 functions and highlighting their potential as therapeutic targets.
-
Journal articleSchilder BM, Murphy KB, Dash H, et al., 2026,
Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.
, Genome MedBACKGROUND: Rare diseases (RDs) are a highly heterogeneous and underserved group of conditions. Most RDs have a strong genetic basis but their causal pathophysiological mechanisms remain poorly understood, limiting the development of targeted therapies. METHODS: We systematically characterised the cell type-specific mechanisms underlying all genetically defined RD phenotypes by integrating the Human Phenotype Ontology (HPO) with whole-body single-cell transcriptomic atlases from embryonic, foetal, and adult samples. Associations were validated against orthogonal biomedical knowledge graphs and then prioritised by strength of supporting evidence, clinical severity, and gene-therapy compatibility. RESULTS: We identified significant associations between 201 cell types and 9,575/11,028 (86.7%) phenotypes across 8,628 RDs, substantially expanding knowledge of phenotype-cell type links. Prioritisation by severity (e.g. lethality, motor or mental impairment) and gene-therapy compatibility (e.g. cell type specificity, postnatal treatability) identified candidate phenotypes and cell types for therapeutic targeting. CONCLUSIONS: We present a scalable, reproducible framework for phenome-wide, cell type-specific mechanism prediction in rare diseases, providing a major step toward systematic therapeutic development for patients across a broad spectrum of serious RDs. SOFTWARE AND DATA AVAILABILITY: Interactive web portal: https://neurogenomics-ukdri.dsi.ic.ac.uk/. R packages introduced in this study: KGExplorer (https://github.com/neurogenomics/KGExplorer), HPOExplorer (https://github.com/neurogenomics/HPOExplorer), and MSTExplorer (https://github.com/neurogenomics/MSTExplorer). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.