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 articleStannard A, Haimov E, Hedley JG, et al., 2026,
Direct evidence and quantification of homologous recognition between DNA duplexes.
, Proc Natl Acad Sci U S A, Vol: 123Stretches of double-stranded DNA sharing the same sequence can recognize each other in cells. This phenomenon, known as homologous recognition, is essential for DNA recombination and repair. Yet, its mechanism remains debated, with purely physical interactions proposed as a contributing factor. Here, we use a minimal DNA nanosensor to quantify homologous pairwise interactions with exquisite precision. We find that homology enhances the duplex-duplex affinity induced by physiological divalent cations and measure the homology-driven recognition free energy as [Formula: see text] per base pair. This affinity substantially enhances coalignment of homologous DNA in the confined geometry of the nanosensor, which mimics physical effects of concentrated biological environments. We introduce a quantitative electrostatic framework that attributes this emergent behavior to coherent charge distributions unique to homologous DNA. Our findings provide compelling evidence in support of purely physical sequence-specific interactions between intact double-stranded DNA, which may bear biological relevance for homologous recombination.
-
Journal articleEvans TRJ, Cook N, El-Khoueiry A, et al., 2026,
A first-in-human, open-label multicentre Phase 1 study of the orally administered E7386 in patients with selected advanced neoplasms
, British Journal of Cancer, ISSN: 0007-0920<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>We present data from the Phase 1 open-label Study 101 of E7386, an oral protein-protein interaction inhibitor reported to block the CBP/β-catenin interaction, in patients with solid tumours.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> Eligible patients (across the UK and US) aged ≥18 years had advanced/recurrent solid tumours (dose-escalation) or <jats:italic>CTNNB1</jats:italic> -mutated hepatocellular carcinoma (dose-expansion). Primary objectives were to assess safety/tolerability and determine the recommended Phase 2 dose (RP2D) of E7386. </jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Thirty-eight patients received study drug (dose-escalation: <jats:italic>n</jats:italic> = 32; expansion: <jats:italic>n</jats:italic> = 6; dose-range: 5–120 mg twice daily [BID]); 60.5% received ≥3 prior anticancer medications. Dose-limiting toxicities (grade-2 lethargy and grade-2 decreased appetite) occurred in 1 patient (20 mg BID cohort). The RP2D was determined as 120 mg BID. Most (94.7%) patients experienced treatment-related adverse events (TRAEs), most frequently nausea (65.8%) and vomiting (60.5%), which were primarily grade 1/2 and well-managed with antiemetics. No grade 4/5 TRAEs were noted. Pharmacokinetic exposure increased with increasi
-
Journal articleLee P-C, Cortellini A, Stefanini B, et al., 2026,
Determinants of long-term survival from atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
, Eur J Cancer, Vol: 240BACKGROUND: Despite the proven superiority against sorafenib, atezolizumab plus bevacizumab (A+B) lacks long-term efficacy data in unresectable hepatocellular carcinoma (uHCC). This study assessed clinicopathologic factors associated with long-term survival with A+B. METHODS: We analyzed patients receiving first-line A+B within AB-Real, a large multicenter registry across Europe, Asia, and the USA. Long-term survivors (LTS) were defined as patients surviving at 24 months. Landmark survival outcomes and associations between baseline clinicopathologic factors and overall survival (OS) were evaluated. RESULTS: Of 1346 patients enrolled, 1085 with Child-Pugh A and ECOG 0-1 received first-line A+B. The median OS was 19.2 months (95% CI: 17.6-20.9), and 2- and 3-year survival rates were 41.4% and 29.3%. Among 695 patients with adequate follow-up, 190 were classified as LTS. The overall response rate was 24.7%, and long-term survivorship was significantly enhanced in radiologic responders (52.2% vs 8.8%, p < 0.001). Compared to non-LTS, LTS more frequently had ALBI grade 1 liver reserve (64.6% vs 38.5%), less PVI (17.9% vs 36.4%), smaller maximum tumor size (3.8 vs 7.0 cm), and lower AFP (median 23.0 vs 240.8 ng/mL) (all p < 0.001). Notably, nearly half (48.8%) of radiologic responders who did not achieve long-term survival had ≥ 2 adverse baseline features, underscoring that tumor burden and liver reserve remain prognostically relevant even among responders. CONCLUSIONS: AB-Real provides the first global real-world evidence of long-term efficacy of A+B in uHCC. Long-term survivorship is enhanced in radiological responders and strongly associated with pre-treatment tumor factors and liver function.
-
Journal articleSakamachi Y, Wiley E, Trempus CS, et al., 2026,
Toll-like receptor 5 protects against murine lung fibrosis through reduced dysbiosis, and TLR5 deficiency is associated with human IPF.
, Sci Transl Med, Vol: 18Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation that results from maladaptive responses to lung epithelial injury; however, the underlying mechanisms remain unclear, and treatment options are limited. Here, we showed that deficiency in the innate immune receptor toll-like receptor 5 (TLR5) is associated with IPF in humans and with increased susceptibility to bleomycin-induced pulmonary fibrosis in mice and that activation of lung epithelial TLR5 through a synthetic flagellin analog protected mice from experimental fibrosis. Mechanistically, epithelial TLR5 activation induced antimicrobial gene expression and ameliorated lung dysbiosis after injury. In contrast, TLR5 deficiency in mice and patients with IPF was associated with lung dysbiosis. Elimination of the microbiome in mice through administration of antibiotics abolished the protective effect of TLR5, and reconstitution of the microbiome by fecal microbiota transplantation rescued the observed phenotype. In conclusion, these studies revealed that TLR5 protects against pulmonary fibrosis through effects on the lung microbiota, providing insight into therapeutic approaches that may ultimately benefit patients with IPF.
-
Journal articleThrush R, Aprile F, 2026,
The sequence grammar and interactions controlling the aging of protein biomolecular condensates
, Current Opinion in Structural Biology, ISSN: 0959-440XBiomolecular condensates play key roles in the cell by organizing and regulating important biochemical processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and stress responses. While these assemblies are typically dynamic, they can undergo time-dependent aging into solid assemblies, which has been linked to pathologies including neurodegenerative disease and cancer. In this review, we focus on the mechanisms that drive condensate aging. In particular, we discuss how features of protein sequence, such as amino acid composition, interaction motifs, and post-translational modifications, influence condensate aging. We further highlight how interactions with RNA and lipid membranes modulate condensate behavior by altering interaction networks and interfacial properties.
-
Journal articleLeung GHD, Bottomley C, Buang N, et al., 2026,
Mapping the plasma proteomic architecture of systemic lupus erythematosus.
, JCI InsightSystemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated module and a renal-associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti-RNP68, anti-RNP-A) was associated with increased interferon-stimulated protein levels (e.g., MX1, ISG15, CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.
-
Journal articleNeeser RM, Igashov I, Schneuing A, et al., 2026,
Flow-based fragment identification via binding site-specific latent representations
, Machine Learning Science and Technology, Vol: 7Fragment-based drug design is a promising strategy leveraging the binding of small chemical moieties that can efficiently guide drug discovery. The initial step of fragment identification remains challenging, as fragments often bind weakly and non-specifically. We developed a protein-fragment encoder that relies on a contrastive learning approach to map both molecular fragments and protein surfaces in a shared latent space. The encoder captures interaction-relevant features and achieves strong discrimination between binding and non-binding regions, reaching ROC–area under the curve values of 0.92 on pocket surfaces and enrichment factors of 22.85 across full protein surfaces. Building on this representation, our generative method LatentFrag produces chemically realistic fragment identities and positions conditioned on the protein surface. LatentFrag improves fragment recovery over docking-based virtual screening, achieving a sampling hit rate more than four times higher at a fraction of its computational cost providing a valuable starting point for fragment hit discovery. We further show the practical utility of LatentFrag and extend the workflow to full ligand design tasks. Together, these approaches contribute to advancing fragment identification and provide valuable tools for fragment-based drug discovery.
-
Journal articleMorgan G, Frattolin J, Elsawah L, et al., 2026,
Excessive shear rate, not shear stress, influences cell mechanical damage in small-bore needle injections
, Journal of Biomechanical Engineering, Vol: 148, ISSN: 0148-0731Cell therapies and 3D bioprinting often require suspended cells to be delivered through needles of 20-gauge and smaller. This often damages cells, affecting their short and long-term viability. Most researchers have attributed this to excessive viscous stresses encountered entering or within the needle, but the experimental evidence contradicts that, as higher viscosity suspension fluids generally yield higher cell viabilities when injected at the same flow rate. We therefore sought to determine the most relevant fluid flow parameter influencing cell mechanical damage. A combination of reprocessing published results and cell injection experiments were conducted. Human umbilical vein endothelial cells (HUVECs) were suspended in Newtonian fluids of varying viscosities and injected through 30-gauge syringe needles in experiments that controlled for either shear stress or shear rate (a kinematic quantity expressing relative velocity of adjacent fluid layers). Based on evidence from injection experiments using a variety of fluids, it is shown that increasing shear rate better explains reductions in cell viability than increasing shear stress. Knowledge that shear rate is a more relevant fluid mechanical parameter governing mechanical damage provides a rational basis for designing injection protocols (injectors and suspension fluid rheological properties) to maximize cell viability.
-
Journal articleShen Y-C, Pinato DJ, Liu T-H, et al., 2026,
Revisiting prophylactic corticosteroids to mitigate severe immune-related adverse events in hepatocellular carcinoma.
, J Hepatol, Vol: 84, Pages: 1178-1182Dual immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) or its ligand (PD-L1) have reshaped the treatment landscape of unresectable hepatocellular carcinoma (HCC). However, their clinical uptake remains limited by the high incidence of severe immune-related adverse events (irAEs), underscoring the urgent need for effective prophylactic strategies. Corticosteroids are traditionally viewed as antagonistic to antitumour immunity and have long been prohibited from prophylactic use in ICI-only regimens. Yet this dogma is increasingly at odds with both clinical practice and emerging evidence. Prophylactic corticosteroids (PC) are routinely administered in patients with lung cancer receiving immunochemotherapy, primarily to prevent chemotherapy-related toxicity. In this context, prophylactic corticosteroids have been associated with a reduction in severe irAEs without compromising efficacy. Our preclinical HCC studies demonstrate that corticosteroid premedication does not impair T-cell activation or antitumour activity induced by dual ICI therapy. Emerging clinical data similarly suggest that baseline or concomitant corticosteroid use does not adversely affect oncological outcomes in HCC. In this Expert Opinion, we argue that it is time to rethink the long-standing prohibition of prophylactic corticosteroids in ICI-based treatment. Judicious prophylactic corticosteroid use may offer a practical means to mitigate severe irAEs - particularly in anti-CTLA-4-containing regimens - while maintaining antitumour activity. We advocate for prospective evaluation of prophylactic corticosteroids in ICI-based regimens associated with higher immune-mediated toxicity, to better define their role in HCC.
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.