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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 articleBennet S, Nagenthiran S, Bainton T, et al., 2026,
Ethanol sclerotherapy versus cystectomy in the management of endometriomata: a systematic review and meta-analysis
, BMC Women's Health, ISSN: 1472-6874BackgroundThe management of endometriomata remains a challenge, with current options associated with either high recurrence rates or significant reduction in ovarian reserve. Ethanol sclerotherapy has been suggested as a treatment that is effective while maintaining ovarian reserve. MethodsPubMed, EMBASE, MEDLINE, SCOPUS and CENTRAL were searched with no restriction on date or language. Keywords and MESH terms for ‘endometrioma’ AND ‘ethanol sclerotherapy’ AND ‘cystectomy’ were used. Studies were included if they made a direct comparison between ethanol sclerotherapy and cystectomy in the management of endometriomata in women of reproductive age. Randomised controlled trials (RCTs), cohort or case control studies were included. Searches were performed 11th February 2025 and repeated 21st August 2025. Risk of bias was assessed using ROB2 for RCTs and ROBINS-I for observational studiesResultsSearches identified 172 studies with 16 of these fitting the inclusion criteria. Unfortunately, a formal analysis of between group change in Anti-Mullerian hormone (AMH) was not possible due to insufficient reporting of change score variance data, as such an exploratory between group pre- and post- analysis was performed instead. This found no significant difference in AMH at baseline (mean difference (MD) 0.02, 95% CI –0.20 to 0.25, p=0.830) while post procedure AMH was significantly higher in the sclerotherapy arm (MD 0.75, 95% CI 0.43 to 1.06, p<0.001). Overall risk of bias was high; however, similar results were seen following a sensitivity analysis excluding studies at highest risk of bias (high for ROB2 and critical for ROBINS-I) (MD -0.25, 95% CI -0.57 to 0.08, p=0.136 and MD 0.60, 95% CI 0.22 to 0.97, p=0.002, respectively). Studies reporting on Antral Follicle Count (AFC) gave conflicting results and all were assessed as at high or critical risk of bias. No significant difference was seen in recurrence (LogOR 0.28, 95% CI &nd
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Journal articleDate A, Wall A, Kiely-Collins H, et al., 2026,
Proteome-wide Target Profiling of alpha-helix Mimetics
, RSC Chemical Biology, ISSN: 2633-0679 -
Journal articleSilva AE, Ferrante G, Silveyra P, et al., 2026, , American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
<jats:title>Abstract</jats:title> <jats:p>Asthma is a heterogeneous disease affecting nearly 300 million people around the world. It is the most common chronic respiratory disease of childhood. There are significant sex differences in asthma incidence, severity, and morbidity around the time of puberty. The reasons for these peri-pubertal changes around the time of puberty are still not fully understood but they are likely multifactorial. In this review, we will discuss several proposed contributing mechanisms, including sex differences in anatomy and development, the effects of sex hormones on airway inflammation and reactivity, the immunomodulatory effects of sex hormones, differences in mucociliary function, and sex differences in genetic and epigenetic factors.</jats:p>
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Journal articleKhor YH, Luppi F, Adegunsoye A, et al., 2026, , Am J Respir Crit Care Med
Acute exacerbations (AEs) occur both in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung disease (fILD). These events confer high morbidity and mortality, with a lack of proven effective therapeutic interventions. The objective of this state-of-the-art document is to summarize latest evidence since the 2016 international working group report on AE-IPF, expanding it across the spectrum of all fILDs. A comprehensive literature review on the epidemiology, associated and risk factors, prognosis, and management of AE-fILD is summarized. In addition to revising the AE definition and diagnostic criteria for broad application across different fILDs, a conceptual framework for acute respiratory worsening (ARW) has been proposed to encompass a variety of acute respiratory deteriorations, both related and unrelated to AE. This allows structured evaluation in both clinical and research settings. The proposed revised definition for AE-fILD is an acute respiratory event characterized by increased respiratory symptoms or signs and associated with radiologic or histologic features consistent with diffuse alveolar damage (with or without superimposed organizing pneumonia) in a patient with known or newly diagnosed fILD. On the other hand, ARW refers to a heterogeneous group of clinical events with acute symptom worsening not attributable to DAD in patients with fILD, such as pulmonary edema, bronchitis, and pneumonia, although severe pneumonia can trigger AE-fILD. Additionally, we discuss considerations for inclusion of AE as a clinical trial endpoint, as well as research priorities for advancing knowledge on the pathogenic mechanisms, event prediction, risk stratification, and development of drugs and supportive treatments.
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Journal articleWu A, Le Floch P, Duverdier A, et al., 2026,
Current research landscape and future prospects of in silico modeling approaches for atopic dermatitis
, JID Innovations, ISSN: 2667-0267Atopic dermatitis (AD) is a chronic, multifactorial inflammatory skin disease with complex, heterogeneous pathogenesis. Understanding its mechanisms, stratifying patients into biologically relevant endotypes, and predicting treatment responses remains challenging if we use empirical approaches alone. In silico approaches, including mathematical modeling, statistical and machine learning methods, enable the dissection of molecular and cellular interactions, identification of key clinical and biological drivers, and extraction of meaningful insights from high-dimensional, noisy datasets, while preserving a systems-level perspective. This review summarizes recent advancements in in silico approaches for AD and outlines strategies to enhance their translational and clinical utility in AD research.
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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 articlePatri S, Agrawal S, Kempen PJ, et al., 2026, , ACS Nano Med, Vol: 1, Pages: 1469-1483
Thermoresponsive nanogels (NGs) can reversibly alter their structure in response to temperature changes. This enables controlled drug release, targeted therapy, and improved treatment precision under physiological or externally applied thermal conditions. Despite these advantages, few studies have systematically tuned the volume phase transition temperature (VPTT) of oligo-(ethylene glycol) methacrylates (OEGMA)-based NGs across physiologically relevant temperatures while maintaining stability and biodegradability. In this work, NGs were synthesized using di-(ethylene glycol) methyl ether methacrylate (DEGMA), tri-(ethylene glycol) methyl ether methacrylate (TEGMA), and 2-methoxyethyl methacrylate (MOEMA) monomers, achieving finely tuned VPTT with a precision within 1 °C. The NGs exhibited diameters ranging from 200 to 350 nm and a negative ζ-potential. Upon reaching the VPTT, the NGs shrank to sizes below 100 nm while becoming monodisperse. Specifically, NG@TEGMA exhibited VPTT between 50-60 °C, NG@DEGMA between 30-45 °C, and NG@TEGMA_DEGMA between 64-66 °C, and NG@TEGMA_MOEMA with molar ratios of 40%, 30%, and 20% displayed VPTT of 37, 47, and 52 °C, respectively. NG@TEGMA NGs were further polymerized with a methacrylated docetaxel derivative, achieving an encapsulation efficiency of 93 ± 4%. These NGs released approximately 90% of the drug upon reaching the VPTT, while nonthermoresponsive controls only released about 20% of the drug. Furthermore, NG@TEGMA demonstrated negligible cytotoxicity and efficient cellular uptake. This study demonstrates a biocompatible and degradable platform of OEGMA-based thermoresponsive NGs for biomedical applications such as hyperthermia-driven drug delivery for cancer therapy with superior thermoresponsive behavior to previously reported OEGMAs-, NIPAM-, or VCL-based NGs.
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