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Journal articleCelsa C, Pressiani T, Nishida N, et al., 2026, , JHEP Reports, Vol: 8, ISSN: 2589-5559
Background & 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
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Journal articleBose A, Bopanna Y, Shetty P, et al., 2026, , Am J Physiol Gastrointest Liver Physiol, Vol: 331, Pages: G125-G139
Hyperactivating mutations in guanylyl cyclase C (GC-C) are monogenic causes of early-onset inflammatory bowel disease, familial diarrheal syndrome, and congenital secretory diarrhea. The mechanisms linking elevated cGMP levels to immune imbalance remain poorly defined. Here, using a preclinical model of a disease-associated GC-C mutation, we observe pleiotropic alterations in the small intestinal epithelium. Transcriptomic and functional analyses revealed impaired Paneth and goblet cell differentiation, compromised barrier integrity, heightened epithelial permeability, and increased proinflammatory cytokine levels. Intestinal organoids from mutant mice exhibited amplified cGMP responses to GC-C ligands and defects in secretory lineage specification, confirming cell-autonomous mechanisms. Strikingly, oral zinc administration suppressed aberrant GC-C activity, normalized cGMP levels, and restored barrier function. These findings highlight the central role of epithelial cGMP signaling in coordinating barrier integrity and immune-epithelial interactions and identify zinc as a tractable therapeutic strategy for GC-C-mediated intestinal disorders.NEW & NOTEWORTHY Activating mutations in GUCY2C, which encodes the receptor guanylyl cyclase C (GC-C), cause early-onset diarrheal disease and gastrointestinal inflammation. Knock-in mice carrying a familial diarrheal syndrome mutation exhibited impaired gut barrier function. Mutant organoids showed defective secretory lineage specification associated with reduced Wnt3 expression. Zinc administration, which lowers epithelial cGMP levels by inhibiting GC-C, reversed most pathological changes in both mice and organoids.
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Journal articleLau R, Giblin S, Sugar A, et al., 2026,
SpyCEP dismantles neutrophil immunity via disorder-drivenchemokine remodeling and GAG targeting
, Proceedings of the National Academy of Sciences of the United States of America, ISSN: 0027-8424Streptococcus pyogenes (Group A Streptococcus; GAS) employs sophisticated virulence strategies to evade human immunity, including secretion of the cell envelope protease SpyCEP, which cleaves and inactivates key neutrophil鈥慳ttracting chemokines such as CXCL8. Here, we integrate cryo鈥慹lectron microscopy (cryo鈥慐M), nuclear magnetic resonance (NMR) spectroscopy, and native mass spectrometry (MS) to investigate how SpyCEP disrupts CXCL8 function. We demonstrate that a disordered aromatic and acidic region within the cleaved autocatalytic maturation loop (CAML) of SpyCEP mimics receptor N-domains and binds an allosteric site on CXCL8. The resulting interaction forms a dynamic fuzzy complex and is coupled to dimer dissociation, consistent with enhanced access to the cleavage site. This disorder鈥憁ediated substrate engagement differs from classical protease mechanisms that rely on rigid recognition interfaces. Additionally, glycan microarray and NMR analyses show that the CAML region mediates glycosaminoglycan (GAG) binding, suggesting a means to recruit SpyCEP and maximize encounters with GAG鈥慹nriched CXCL8 reservoirs. Together, these findings provide a structural and biophysical framework for understanding how SpyCEP combines substrate engagement with GAG targeting to dismantle chemokine gradients and inhibit neutrophil recruitment. More broadly, this work highlights the role of intrinsic disorder in protease recognition and suggests new avenues for anti鈥憊irulence therapies and vaccine strategies targeting SpyCEP.
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Journal articleShmool TA, Lartigue N, Liu X, et al., 2026, , ACS Mater Au, Vol: 6, Pages: 831-840
Biopolymer-based hydrogels are attractive therapeutic carriers, offering tunable physicochemical properties and therapeutic release kinetics. Major limitations include low rheological strength, poor physical and thermal stability, limited swelling, and achieving controlled therapeutic delivery. To address these challenges, a library of innovative metal-organic framework (MOF)-biopolymer-based hydrogels was developed. The MOFs, zeolitic imidazole framework-8 (ZIF-8), and zinc adeninate framework (ZAF) were integrated into chitosan/alginate (C/A) and chitosan/gelatin (C/G) hydrogels, at increasing chitosan content. The MOF-hydrogels presented distinct immunoglobulin G (IgG) release rates and greater rheological strengths, swelling capabilities, and thermostabilities compared to the MOF lacking hydrogels. The MOF-C/A-hydrogels showed higher rheological strengths compared to the MOF-C/G-hydrogels. The ZIF-8-hydrogels presented greater rheological strengths, yet lower thermostabilities, and higher IgG release rates compared to the ZAF-hydrogels. This is attributed to the greater flexibility of ZAF, containing bulky adenine groups, which could lead to steric hindrance and limited zinc ion-dipole interactions. Holistically, exploiting ion-dipole, electrostatic, and hydrogen bonding interactions between the MOFs and biopolymers enabled therapeutic release rate control and balanced the typical trade-off between hydrogel swelling and rheological strength. The MOF-hydrogels offer adaptable platforms, advancing the design of next-generation MOF-biopolymer-based carriers for target applications.
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Journal articleHorzum U, Oberacher H, Haun M, et al., 2026, , Signal Transduct Target Ther, Vol: 11
Multiple myeloma (MM) is characterized by the production and secretion of large quantities of immunoglobulins, making this malignancy highly dependent on mechanisms that maintain cellular proteostasis. While significant clinical progress has been made by targeting the degradative branch of proteostasis, much less attention has been given to the biosynthetic branch. In this study, we demonstrated that inhibiting COPII-dependent endoplasmic reticulum (ER) export induces cell death in several MM cell lines and primary patient-derived cells. The induction of cell death was dependent on the secretory status of MM cells. Blocking ER export in secretory MM cells caused the accumulation of misfolded proteins, which activated ER-associated degradation (ERAD). Consequently, we observed an ERAD-dependent increase in the levels of free cytosolic amino acids and a subsequent activation of mTORC1 signaling. Simultaneously, we observed mitochondrial dysfunction. These alterations resulted in a mismatch between the increased energy demand due to mTORC1 activation, and the disrupted energy supply from mitochondrial impairment. This energetic imbalance results in homeostatic collapse and cell death of secretory MM cells. The therapeutic potential of the concept was demonstrated in two in vivo myeloma models. These findings suggest that the ER export machinery could be a promising therapeutic target in multiple myeloma.
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Journal articleWells C, Rosewarne C, Taylor K, et al., 2026, , Design for Health, Pages: 1-13, ISSN: 2473-5132
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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.
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Journal articleLeung AS-Y, Tham EH, Yamamoto-Hanada K, et al., 2026, , Allergy
BACKGROUND: IgE-mediated food allergy prevention guidelines are now established in many countries, but their implementation in routine clinical practice globally remains unclear. METHODS: An anonymous online survey was distributed to healthcare professionals (HCPs) through the World Allergy Organization network between December 2024 and April 2025, collecting data on food allergy prevention recommendations in daily clinical practice. RESULTS: The analysis included 731 healthcare professionals from 80 countries worldwide: Asia (36.7%), Europe (27.1%), North America (15.9%), and Rest of the World (20.0%; Russia, South America, Africa, Oceania). Unsupervised clustering revealed two distinct practice patterns-one favoring early allergen introduction and one favoring later introduction-with timing varying by allergen type. For peanuts, clusters diverged between early (median 6 months of age) and late (median 18 months of age) introduction recommendations for high-risk infants. Allergen introduction timing was independently driven by region and specialty: North American HCPs recommend peanut introduction 6.7 months earlier than those in Asia (5.48 ± $$ \pm $$ 3.32 vs. 12.18 ± $$ \pm $$ 7.27 months; p < 0.001), and pediatric allergists globally advocate for introduction 2.37 months earlier than non-allergists (8.72 ± $$ \pm $$ 5.85 vs. 11.09 ± $$ \pm $$ 7.14 months, p = 0.024). This disparity is more pronounced in high-risk infants than in normal-risk infants. CONCLUSIONS: The variability in allergen introduction practices, driven by geography and medical specialty, highlights a persistent gap in prevention guidelines adoption. This divergence likely reflects both suboptimal implementation of existing recommendations and regional differences in food allergy epidemiology. These findings underscore the need for population-tailored allergen introduction strategies acro
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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.
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Journal articleWatt F, Liang J, 2026,
Systemic biomarkers of treatment response to methotrexate in people with painful knee osteoarthritis: a biological substudy of the PROMOTE randomised controlled clinical trial
, Osteoarthritis and Cartilage, ISSN: 1063-4584Objective: Stratification of therapeutic responses may help identify efficacious therapies for osteoarthritis (OA). In the PROMOTE randomised trial, participants with elevated baseline high-sensitivity C-reactive protein (hs-CRP) showed greater pain reduction after methotrexate treatment. We set out to interrogate a broader panel of serum/plasma inflammatory response markers relevant to methotrexate actions as potential biomarkers of therapeutic effect. Our objectives were to: (i) characterize changes in these systemic markers during methotrexate treatment; determine whether (ii) baseline levels or (iii) changes in any marker during treatment were associated with treatment response; and (iv) compare these findings with the more established clinical inflammatory marker, hs-CRP. Design: Plasma/serum samples from participants in PROMOTE’s biological substudy were analysed for 35 inflammatory markers at baseline (pre-treatment) and at 6-months (post-treatment), by MesoScale V-plex multiplex assay. Those with paired biological and clinical data at both baseline and 6-months were included in the substudy analysis set. Relationships between markers and overall data structure were assessed by Pearson correlation and Principal Component analysis. Associations between markers (baseline levels or change over time) and change in average knee pain severity in past week (numerical rating scale, NRS) were evaluated by univariable linear regression, adjusting for baseline age, sex, and body mass index. Least Absolute Shrinkage and Selection Operator (LASSO) regression with bootstrap resampling enabled marker selection. Benjamini Hochberg correction adjusted for multiple testing (Padj). Results: 87 participants with paired blood marker and clinical data were eligible for substudy analysis.18/35 markers were quantifiable and analysed. Systemic IL-8 and TNF-α levels decreased (Padj=0.015, 0.048 respectively) while IL-15 increased (Padj=0.033) with methotrexate treatment ov
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