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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
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Journal articleHabiburrahman M, Masrour N, Patel N, et al., 2026,
Clinical validation of a DNA methylation biomarker associated with overall survival of relapsed ovarian cancer patients
, International Journal of Cancer, Vol: 158, Pages: 1821-1835, ISSN: 0020-7136Approximately 70% of ovarian cancer (OC) patients relapse after chemotherapy, underscoring the need to assess survival before second-line treatment. We previously identified PLAT-M8, an 8-CpG blood-based methylation signature linked to chemoresistance. This study validates its correlation with clinicopathological features and treatment profiles in additional cohorts. Extracted DNA from whole blood was provided from the BriTROC-1 (n = 47) and OV04 cohorts (n = 57) upon the first relapse. Additional samples from Hammersmith Hospital (n = 100) were collected during first-line chemotherapy (Cycles 3–4 and 6). Bisulphite pyrosequencing was used to quantify DNA methylation at the previously identified 8 CpG sites. The methylation data obtained were combined with previous data from ScoTROC-1D and 1V (n = 141) and OCTIPS (n = 46). Cox regression was used to assess OS after relapse concerning clinicopathological characteristics. The DNA methylation Class (Class 1 vs. 2) was determined by consensus clustering. As for results, blood DNA methylation at relapse correlates with clinical outcomes, but it has no impact during first-line treatment. Class 1 is linked to shorter survival (summary OS: HR 2.50, 1.64–3.79) and poorer prognosis on carboplatin monotherapy (OS: aHR 9.69, 95% CI: 2.38–39.47). It is associated with older (>75 years), advanced-stage, platinum-resistant patients, residual disease, and shorter PFS. In contrast, Class 2 is linked to platinum sensitivity, higher complete response rates (RECIST), and better prognosis but shows no correlation with CA-125. These findings highlight PLAT-M8's potential in guiding second-line chemotherapy decisions. The PLAT-M8 methylation biomarker is associated with survival in relapsed OC patients and may potentially predict their response to second-line platinum treatment.
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Journal articleGrant B, Kean J, de Silva NL, et al., 2026,
Clinical features of androgen abuse withdrawal in men during the first year of cessation: a community dwelling study.
, J Clin Endocrinol MetabCONTEXT: Androgen abuse is an increasing public health concern, particularly among young men seeking muscular or image enhancement. Although most achieve biochemical recovery within 12 months of cessation, mood disturbances, sexual dysfunction, and fatigue is widely reported for years afterward. OBJECTIVE: To examine symptom severity the relationship to biochemical recovery during the first year after androgen abuse cessation. METHODS: We conducted a cross-sectional study of community-dwelling men grouped as non-users, current users, or past users who had ceased within the last 12 months. Participants completed questionnaires on androgen and substance use and four validated instruments assessing mood (BDI-II), anxiety (GAD-7), sexual function (IIEF-15), and quality-of-life (SF-36). Morning fasted serum hormonal analysis and screening to exclude undisclosed androgen use were performed. RESULTS: 247 men were included: 50 non-users, 125 current users, 72 past users. Self-reported psychiatric diagnoses were 2.5-fold higher among current and past users than non-users. Total testosterone was highest in current users (p<0.001) with no difference between past and non-users. Past users reported significantly worse mood, anxiety, sexual function, and quality of life versus non-users. Multivariable analyses showed psychiatric comorbidity was independently associated with depression (p=0.001), anxiety (p<0.001), and poorer quality-of-life (p<0.05). Older age and higher LH were associated with reduced sexual function (p<0.05), while lower testosterone showed only a modest association with depressive symptoms (p=0.03). CONCLUSION: Among men in the first year after stopping androgen abuse, psychological symptoms and reduced quality-of-life were most strongly associated with psychiatric comorbidity than biochemical recovery. These findings challenge the assumption that androgen withdrawal symptoms are predominantly driven by hypogonadism, and supports developing psychol
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Journal articleMalik TH, Kwiatkowska K, Lomax-Browne HJ, et al., 2026,
A novel fusion protein reduces kidney complement in experimental C3 glomerulopathy.
, Clin Exp ImmunolINTRODUCTION: Complement activation contributes to kidney damage in many types of glomerulonephritis and complement inhibition therapy is approved for IgA nephropathy and C3 glomerulopathy. However, inhibition is not specific to the kidney resulting in unnecessary systemic complement inhibition and increased infection risk. METHODS: To develop an effective inhibitor of glomerular complement we combined complement factor H-related protein 5 (FHR51-9), which binds to glomerular complement C3, with the complement regulatory domains of the key negative regulator of C3 activation, complement factor H (FH1-5). RESULTS: One week after adeno-associated virus (AAV) mediated expression of the FHR51-9FH1-5 fusion protein in factor H-deficient mice, glomerular C3b/iC3b/C3c was significantly reduced and properdin resolved completely compared to controls. There was no change to circulating C3 levels and FHR51-9FH1-5 was detected in glomeruli in association with C3d. Six and twenty weeks after AAV8-FHR51-9FH1-5 treatment in hFH-FHR5mut mice (a mouse model of CFHR5 nephropathy) glomerular C3b/iC3b/C3c, C3d and C5 were significantly reduced and properdin resolved completely compared to controls. Pre-administration of AAV-FHR51-9FH1-5 also ameliorated abnormal glomerular C3b/iC3b/C3c, C3d, C5 and properdin in a triggered CFHR5 nephropathy model. In vitro FHR51-9FH1-5 showed dose-dependent binding to surface-immobilised C3, C3b, iC3b and C3d; factor I cofactor activity; and reduced C3a generation in an alternative pathway convertase assay. CONCLUSIONS: Taken together, the FHR51-9FH1-5 protein reduced glomerular C3 in experimental models of C3 glomerulopathy driven by either factor H deficiency or mutated FHR5. These preclinical data indicate that FHR51-9FH1-5 protein represents a novel treatment strategy for complement-mediated kidney disease.
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Journal articleRasmussen AB, Swann OC, Brown JC, et al., 2026,
Influenza A virus polymerase co-opts distinct sets of host proteins for RNA transcription or replication.
, Cell Chem BiolThe influenza A virus polymerase, consisting of a heterotrimer of three viral proteins, carries out both transcription and replication of the viral RNA genome. These distinct activities are regulated by viral proteins and various co-opted host cell proteins, which serve as targets for the development of novel antiviral interventions. However, little is known about which host proteins direct transcription versus replication. In this report, we performed a differential interactome screen to identify host proteins co-opted downstream or upstream of primary transcription, some of which may be transcription- or replication-specific factors. We found that distinct sets of host proteins interact with the influenza polymerase as it carries out the different activities. We functionally characterized HMGB2 and RUVBL2 as replication cofactors and RPAP2 as a transcription cofactor. Our data demonstrate that comparative proteomics can be used as a targeted approach to uncover virus-host interactions that regulate specific stages of the viral life cycle.
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Journal articleMuraro PA, De Matteis E, Scalfari A, 2026,
A tight match: comparing the effectiveness of immune reconstitution therapies for multiple sclerosis.
, Brain, Vol: 149, Pages: 704-706 -
Journal articleWang Z, Dunican C, Dayananda P, et al., 2026,
Comparative cross-species transcriptomics during RSV infection identifies targets to treat RSV disease
, Journal of Infection, Vol: 92, ISSN: 0163-4453Respiratory syncytial virus (RSV) remains a health threat to young children worldwide. The host immune response plays a key role in disease following infection. Infection models advance our understanding of respiratory viruses, but individual models have gaps, which overlapping complementary systems can fill. We compared disease signatures in mice, adults and children; combining transcriptomic data collected from blood, nasal mucosa and lung biopsy following RSV infection. We identified both shared and species-specific pathways triggered by RSV. While systemic responses in children’s blood were more similar to those in RSV-challenged adults, mucosal responses during primary infection in mice more closely resembled those in children. We identified an association between IL-17 pathways and RSV pathogenesis and with over-expression of the downstream effectors S100A8 and S100A9. Inhibiting these with the anti-inflammatory drug Paquinimod reduced disease. Here we demonstrate that integrating mouse and human transcriptomic data can identify novel targets to treat RSV disease.
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Journal articleTam KMM, Brown NC, Bronstein M, et al., 2026,
Learning constrained static equilibrium for thrust network inverse form-finding via physics-informed geometric deep learning on CW complexes
, Advanced Engineering Informatics, Vol: 70, ISSN: 1474-0346This work integrates Geometric Deep Learning (GDL) with physics-informed modelling to approximate solutions to a constrained, ill-conditioned, and nonlinear inverse shell form-finding problem across diverse geometries and patterns. Given a target geometry and pattern design as meshes, the proposed neural framework predicts a funicular shell—defined by edge forces and vertex positions—that satisfies static equilibrium and closely matches the target form. Three main contributions are introduced: (1) a relaxed, numerically stable physics objective using efficient differentiable graph operators to mitigate the ill-conditioning of the nonlinear problem; (2) a stochastic augmentation strategy that enriches training with geometries of varying funicular feasibility, enhancing generalisation to infeasible inputs; and (3) a hierarchical GDL architecture that learns directly from irregular n -gon surface meshes, modelled as cell complexes to incorporate vertex, edge, and face features in both inputs and outputs. This approach eliminates the need for simplification of graph datastructures common in existing methods, improving mesh modelling versatility. Extensive studies examine the numerical stability of physics formulations, robustness for out-of-distribution designs, and the expressivity of the GDL architecture. While focused on a specific inverse form-finding task, this work offers general insights into addressing ill-posed inverse problems, showing how physics-based learning can support optimisation of mesh-based architectural structures under variable connectivity and design constraints.
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Journal articlePuttur F, Lloyd CM, 2026,
Sex Differences in Lung Immunity.
, Immunol Rev, Vol: 338Biological sex has a significant impact on how the immune system develops and responds to foreign and self-antigens. Sex differences exist in innate and adaptive immune cells, both at homeostasis and in the context of infection and inflammatory diseases such as asthma, cancer, and autoimmune disorders. Women generate stronger immune responses and are more susceptible to developing autoimmune conditions, while males are more prone to acute viral infections and developing certain cancers. Some immunological differences persist throughout life, while others emerge only after puberty and before reproductive senescence. Additionally, environmental exposures can affect the influence of biological sex in regulating immune function. This is particularly pertinent at mucosal surfaces such as the lungs, where lung immune defenses are constantly exposed to foreign material during respiration. Consequently, environmental factors together with genetics, age and sex hormones play a vital role in governing lung tissue immune responses between the sexes. In this context, we highlight studies that support the need for considering sex as an important biological variable in lung immunological research. This knowledge will provide a benchmark for understanding sex-driven immunological mechanisms that underpin disease development and may inform new avenues targeted for generating sex-specific therapies in lung disease.
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Journal articleDiaz LA, Ajmera V, Arab JP, et al., 2026,
An Expert Consensus Delphi Panel in Metabolic Dysfunction- and Alcohol-associated Liver Disease: Opportunities and Challenges in Clinical Practice.
, Clin Gastroenterol Hepatol, Vol: 24, Pages: 633-645.e4BACKGROUND & AIMS: Metabolic dysfunction- and alcohol-associated liver disease (MetALD) is a recently defined entity for individuals with liver steatosis, metabolic dysfunction, and increased alcohol intake. However, the current definition of MetALD poses multiple challenges in clinical practice and research. In this Delphi consensus, we provide practical recommendations for the clinical assessment and management of MetALD to address current clinical challenges in MetALD. METHODS: We used a modified Delphi process, including 2 surveys involving a panel of 28 experts from 10 countries spanning 4 continents. We predefined consensus as requiring an ≥80% agreement. RESULTS: The panel reached consensus on 28 statements. Recommendations emphasize the importance of a comprehensive assessment of patients with presumed MetALD, including the quantification of alcohol intake using validated questionnaires and the use of objective biomarkers of alcohol use, such as phosphatidylethanol. The need to reassess metabolic risk factors and liver disease after a period of alcohol abstinence was highlighted to distinguish the primary driver of liver injury. Noninvasive tests were recommended to assess liver disease severity, whereas routine liver biopsy was deemed unnecessary unless other diagnoses were suspected. Comprehensive management strategies should involve multidisciplinary care focusing on lifestyle modifications, alcohol reduction or cessation, weight loss, and exercise. Finally, the panel identified significant gaps in knowledge, advocating for standardized research protocols, longitudinal studies, exploration of pathophysiological mechanisms to inform precision medicine approaches, and the validation of quantitative alcohol biomarkers for identifying MetALD. CONCLUSIONS: This Delphi consensus provides clear recommendations for the clinical assessment and management of MetALD, addressing the unique challenges posed by this condition.
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