Results
- Showing results for:
- Reset all filters
Search results
-
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
-
Journal articleLee P-C, Cortellini A, Stefanini B, et al., 2026, , Eur J Cancer, Vol: 240
BACKGROUND: 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鈥<鈥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鈥痗m), and lower AFP (median 23.0 vs 240.8 ng/mL) (all p鈥<鈥0.001). Notably, nearly half (48.8%) of radiologic responders who did not achieve long-term survival had ≥鈥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 articleMorgan G, Frattolin J, Elsawah L, et al., 2026, , Journal of Biomechanical Engineering, Vol: 148, ISSN: 0148-0731
Cell 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 articleBedwani NH, Leung PKH, Zen J, et al., 2026,
Measurement of immune cell-derived volatile organic compounds from ex vivo and in vitro cultures: a scoping review
, Metabolomics, ISSN: 1573-3882Background:Volatile organic compounds (VOCs) originate from cellular metabolic activity and disease-related biochemical processes and are emerging as non-invasive biomarkers. Although immune cells undergo marked metabolic and functional reprogramming during activation and differentiation, their contribution to the cellular volatile metabolome remains poorlycharacterised. Aim of Review: This scoping review aims to systematically map experimental studies reporting untargetedVOCs emitted from mammalian immune cell cultures, with particular emphasis on volatilomics workflows and confidence in metabolite identification. Key Scientific Concepts of Review: A systematic literature search identified experimental studies analysing headspace VOCs fromprimary and immortalised immune cells. Data were extracted on cell models, stimulation conditions, headspace sampling strategies, analytical platforms and data processing workflows. Analytical quality and confidence in compound assignment were assessed using the Chemical Analysis Working Group–Metabolomics Standards Initiative (CAWG-MSI) criteria. Eleven studies met the inclusion criteria, employing a heterogeneous range of sampling and analytical approaches, including solid-phase microextraction, sorbent-based thermal desorption and secondary electrospray ionisation coupled to high-resolution mass spectrometry. Across studies, reported VOC profiles were able to distinguish immune cell type, activation state and external stimuli, supporting the biological plausibility of immune-derived volatilomic signatures. However, substantial methodological variability was evident. Only one study achieved CAWG-MSI level 1 identification, and most lacked key metadata,internal standards or validation procedures. Overall, immune cells appear to emit distinct VOC signatures linked to immunometabolic state, but current practices limit reproducibility, cross-study comparability and confident biological interpretation. This review identifiesmet
-
Journal articleGui L, Armstrong A, Adjiman CS, et al., 2026, , Phys Chem Chem Phys
Many chemical reactions occur in the liquid phase, making the accurate prediction of the liquid-phase activation Gibbs free energy, Δ≠G°,L, crucial for numerous applications. Quantum mechanical (QM) methods with implicit solvation models offer a valuable route to Δ≠G°,L prediction, although they are computationally demanding at high levels of theory and for larger systems. Data-driven surrogate models can address this issue but require extensive training and test datasets. We present here the liquid phase reaction energy database (LiPRED-2026), a QM reaction database containing 4513 Δ≠G°,L values for 28 diverse chemical reactions computed in various solvents at 298.15 K. The reactions have been chosen for their sensitivity to solvent effects and the availability of experimental data. The SMD model is employed to calculate solvation contributions to Δ≠G°,L because it can be used to account for the effect of solvent on the geometries of the reactants and transition states and it is suitable for charged species. The database contains Δ≠G°,L obtained from seven calculation methods, including the thermodynamic cycle method, the direct method, and their variants. Using a subset of the database, a benchmarking study shows that the best methods achieve a mean absolute error of 2.89 kcal mol-1 in absolute Δ≠G°,L and 1.00 kcal mol-1 in relative Δ≠G°,L, respectively, with the lower error for the relative Δ≠G°,L being mainly attributable to error cancellation. The use of a higher level of theory to calculate Δ≠G°,L improves relative Δ≠G°,L values only, but not absolute ones. These results provide valuable insights into the choice of methods and levels of theory appropriate for calculating Δ≠G°,L, while the database can serve for training and testing surrogate models.
-
Journal articleSerrano-Serrano ML, Godfried Sie C, Bechter O, et al., 2026, , Cancer Res Commun
The BRAF V600 mutation confers a poor prognosis in metastatic colorectal cancer (mCRC). Mosperafenib is a novel, paradox-breaking BRAF inhibitor (BRAFi). In this analysis of a phase 1 study (ISRCTN13713551), we evaluated circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker for mosperafenib monotherapy in BRAF V600-mutant mCRC. We analyzed 49 biomarker-evaluable mCRC patients (BRAF V600 mutant; 23 BRAFi-naive, 26 BRAFi-experienced). Plasma samples were collected at baseline and longitudinally. ctDNA levels were quantified using tumor-naive and tumor-informed assays and correlated with RECIST 1.1 response and progression-free survival (PFS). Mutational profiles were assessed to identify resistance mechanisms. Low baseline ctDNA (≤10% tumor fraction) was prognostic for longer median PFS (mPFS) (284 vs. 59 days; HR=0.32, p=0.00051). Early ctDNA dynamics were highly predictive; a ≥75% ctDNA reduction at C1D15 ("molecular response") correlated with longer mPFS (281 vs. 43 days, p<0.0001). This molecular response occurred in all BRAFi-naive patients versus 48% of BRAFi-experienced. Pre-existing MAPK pathway resistance mutations were prevalent and prognostic for poor outcomes in the BRAFi-experienced cohort (HR=3.5, p=0.003), while BRAFi-naive patients acquired these at progression. CtDNA is a powerful biomarker for mosperafenib-treated BRAF V600-mutated mCRC. Low baseline ctDNA is highly prognostic, while an early, deep molecular response at C1D15 predicts durable benefit. This response is largely confined to BRAFi-naive patients, as pre-existing MAPK pathway alterations in BRAFi-experienced patients correlate with lack of response. These findings support using early ctDNA dynamics as an efficacy endpoint in future trials.
-
Journal articleChamai M, Jebreel WMA, Kabuya J-BB, et al., 2026, , Expert Rev Anti Infect Ther
-
Journal articleSaber SH, Yak N, Dolski K, et al., 2026, , Nat Commun
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. The emergence of viral mutations that diminish the effectiveness of current interventions underscores the importance of alternative, host-directed strategies. Here, we show that pharmacological inhibition or knockdown of host N-myristoyltransferase 1 (NMT1), one of the two human enzymes that mediates protein N-myristoylation, significantly impairs SARS-CoV-2, Vesicular Stomatitis Virus (VSV) and Respiratory syncytial virus (RSV) infections. We demonstrate the antiviral efficacy and safety of this host-directed therapeutic strategy across multiple viral tropic sites, including human lung adenocarcinoma cell lines, primary nasal epithelial cells, and human choroid plexus-cortical brain organoids. NMT1 inhibition triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, through endoplasmic reticulum and lysosomal structures, which leads to perturbed progeny virion composition and spike maturation, impairing progeny virion infectivity.
-
Journal articleVieito M, Fontana E, Han CH, et al., 2026, , J Clin Oncol, Vol: 44, Pages: 1337-1348
PURPOSE: BRAF V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity. PATIENTS AND METHODS: This phase Ia/b study was conducted in patients with advanced solid tumors harboring a BRAF V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and/or recommended phase II dose(s). RESULTS: Eighty patients (60% BRAFi-exposed)-63 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors-received ≥1 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition ≥90%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day). CONCLUSION: Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-naïve and BRAFi-expos
-
Journal articleChen S-Y, Bennett J, Navaratnam N, et al., 2026, , Biochem J, Vol: 483, Pages: 621-637
AMP-activated protein kinase (AMPK) plays an important role in maintaining energy homeostasis in mammals. AMPK is a heterotrimer of an α catalytic subunit and two regulatory subunits, β and γ. In mammals, each subunit has different isoforms (α1/α2, β1/ β2, and γ1/γ2/γ3) encoded by separate genes, leading to the potential expression of 12 AMPK complexes. Here, we show that AMPK containing the long forms of γ2 (γ2a, encoding a protein of 569 amino acids, and γ2c, 525 amino acids) binds to 14-3-3. In contrast to AMPK containing the short form of γ2 (γ2b, 328 amino acids), bacterial expression of AMPK containing the long forms of γ2 requires co-expression with 14-3-3 and prior phosphorylation of Thr172 within the α subunit. AMPKγ2-14-3-3 complexes have reduced activity compared with AMPKγ1 or AMPKγ2b but retain allosteric activation by AMP and the AMPK activator, 991. We found that two predicted 14-3-3 binding sites within γ2a (T97 and S122) were phosphorylated in the bacterially expressed AMPK complex. Furthermore, we show that a peptide spanning these two phosphorylated sites binds to 14-3-3 in vitro and determined the crystal structure of this 14-3-3-peptide co-complex. These results indicate that 14-3-3 binds to the N-terminal region of γ2a/c, reducing the activity of AMPK relative to AMPKγ1 and AMPKγ2b. Our findings reveal a new mode of regulation of AMPK containing the long forms of γ2. While the biological significance of 14-3-3 binding to AMPKγ2a/c complexes remains to be determined, our studies provide the starting point to begin to address this issue.
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.