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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 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.
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Journal articleKalafateli M, Sena Aydin B, Polat B, et al., 2026, , Frontline Gastroenterology, Vol: 17, Pages: 250-261, ISSN: 2041-4145
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide with high morbidity and mortality rates. An early diagnosis, in primary care, seems paramount, especially in the high-risk patients with type 2 diabetes or/and obesity. As we thoroughly discuss in this review, the diagnosis and staging of MASLD has extensively evolved during recent years, especially with the introduction of non-invasive tests (NITs) in our management. According to current guidelines, a multi-tier diagnostic system is implemented in primary care in high-risk groups: the first step includes a non-patented blood test, such as Fibrosis score-4 (FIB-4), followed by an imaging modality such as transient elastography (TE) or a test based on collagen formation such as enhanced liver fibrosis test (ELF). In a specialty setting, several NITs for the diagnosis of steatosis, steatohepatitis and fibrosis, as well as for the prediction of clinical outcomes, have been developed and validated - with various performances - aiming to replace liver biopsy and to guide management decisions. However, NITs have certain limitations, particularly when applied to the general population. Further research is needed to refine and validate both existing and novel biomarkers to reliably guide stage and prognostication in this cohort.
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Journal articlePierret ACS, Patel AH, Daniels E, et al., 2026, , Andrology, Vol: 14, Pages: 1002-1016, ISSN: 2047-2919
The hypothalamic–pituitary–gonadal axis is regulated by the gonadotropin-releasing hormone pulse generator in the hypothalamus. This is comprised of neurons that secrete kisspeptin in a pulsatile manner to stimulate the release of GnRH, and, in turn, downstream gonadotropins from the pituitary gland, and subsequently sex steroids and gametogenesis from the gonads. Many reproductive disorders in both males and females are characterized by hypothalamic dysfunction, including functional disorders (such as age-related hypogonadism, obesity-related secondary hypogonadism, hyperprolactinemia, functional hypothalamic amenorrhea and polycystic ovary syndrome), structural pathologies (such as craniopharyngiomas or radiation or surgery-related hypothalamic dysfunction), and pubertal disorders (constitutional delay of growth and puberty and congenital hypogonadotropic hypogonadism). However, in many of these conditions, the relative contribution of hypothalamic dysfunction to the observed hypogonadism is unclear; as to date, there is no direct method of evaluating hypothalamic reproductive function in humans. Indeed, it is not possible to directly measure gonadotropin-releasing hormone levels in the hypothalamo-pituitary portal vessels, such that secondary (i.e., pituitary dysfunction) and tertiary (i.e., hypothalamic dysfunction) hypogonadism are often conflated as one entity. In this review, we examine the evidence for the use of kisspeptin as a method of directly evaluating hypothalamic reproductive dysfunction, and deliberate its potential future role in the evaluation of pubertal and reproductive disorders.
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Journal articleWallace DV, Hossny EM, Levin M, et al., 2026, , Immunol Allergy Clin North Am, Vol: 46, Pages: 233-256
This article compares 12 national and international anaphylaxis guidelines published between 2006 and 2025, highlighting evolving methodological frameworks, diagnostic criteria, and treatment approaches. While consensus supports prompt epinephrine use, differences remain in definitions, risk stratification, and post-acute care. Gaps in education, early childhood care protocols, and global harmonization continue to exist. The analysis emphasizes the shift from crisis-based to proactive anaphylaxis management and underscores the need for equity-focused, evidence-based interventions.
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Journal articleFarias A, Bridgeman VL, Rodrigues FS, et al., 2026, , Proc Natl Acad Sci U S A, Vol: 123
Metastatic breast cancer accounts for 7% of cancer-related deaths, with the lungs being a common site of cancer spread. In parallel, lower respiratory tract infections, including those caused by respiratory syncytial virus (RSV), remain a common cause of morbidity and mortality worldwide. Acute viral respiratory infections induce marked changes in the lung. However, how these changes influence metastasis initiation and cancer progression remains unclear. Using breast cancer and other cancer cell types in an experimental lung metastasis model, we show that RSV infection impairs tumor cell seeding and early growth in the lung, resulting in fewer metastatic nodules. We demonstrate that restriction of metastatic spread is due to alterations in the lung environment mediated by RSV-induced type I interferons (IFNs). Consistent with this idea, intranasal administration of recombinant IFN-α is sufficient to recapitulate the anti-metastatic effect of RSV infection. Using single cell RNA sequencing supported by in vivo and ex vivo validation, we show that IFN-α influences interactions between epithelial/endothelial cells and cancer cells. Furthermore, both RSV infection and IFN-α administration trigger marked local and systemic upregulation of Galectin-9, an IFN-inducible protein associated with acute respiratory infection in humans. Treatment of cancer cells with Galectin-9 alone is sufficient to restrict metastatic seeding. Altogether, our results suggest that type I IFNs induced by respiratory virus infection render the lungs less permissive to cancer cell seeding and consequently interfere with the ability of tumor cells to successfully initiate metastatic colonization.
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Journal articleMohammed Abdul Wajid L, Saglani S, Nagakumar P, et al., 2026, , Arch Dis Child, Vol: 111, Pages: 444-448
OBJECTIVE: This study aimed to explore health professionals' perspectives on the management of preschool wheeze, including their views on using tests to guide treatment for children with recurrent wheeze. DESIGN: Purposive and snowball sampling were used in this qualitative study to recruit health professionals with experience of managing children with pre-school wheeze from primary and secondary care settings across England. Semi-structured interviews were conducted via Microsoft Teams. Transcripts were analysed thematically, supported by the use of NVivo software, to identify key themes. RESULTS: 14 health professionals participated: four general practitioners, four general paediatricians, four hospital asthma nurses, one tertiary respiratory paediatrician and one primary care nurse. Participants agreed that preschool wheeze remains a significant disease. Thematic analysis identified four key themes: (1) challenges with diagnostic terminology, where a lack of consistent terminology was considered to impact communication and management; (2) diagnostic uncertainty, where the absence of objective tests for early asthma diagnosis negatively contributed to management plans; (3) current practice of investigating children with preschool wheeze, where participants described a lack of infrastructure and approach to performing tests in primary and secondary care; and (4) treatment considerations in which parents' medication beliefs were thought to influence adherence to prescribed treatments. There were differences in the views regarding the management of preschool wheeze between primary and secondary care professionals. CONCLUSION: Health professionals' views highlight inconsistent use of diagnostic terminology for preschool wheeze, contributing to variation in management. Integrated care pathways and infrastructure are urgently needed to improve outcomes for children with preschool wheeze.
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Journal articleBellamkonda A, Sherin PS, Kench T, et al., 2026, , Chem Sci, Vol: 17, Pages: 7018-7026, ISSN: 2041-6520
DNA can fold into a range of different structures besides the canonical double helix. These structures have been shown to play important biological regulatory roles, highlighting that is not only DNA's sequence but also its structure that dictates its functions. However, detecting and visualising these structures in cells is challenging, due to their dynamic nature and low abundance at any one time, as compared to duplex DNA. In this paper we report the syntheses of three new platinum(ii) complexes, coordinated to C^N^N^C and N^C^C^N ligands, and study their photophysical properties in the absence and presence of duplex and quadruplex DNA structures. We find that two of the probes switch on their phosphorescence intensity upon interaction with DNA. Moreover, we demonstrate that the phosphorescence lifetime of one of the probes shows distinct changes upon interaction with quadruplex DNA, as compared to duplex DNA or free in solution. Reassuringly, this probe shows no self-aggregation in the nuclei and nucleoli of live and fixed cells, allowing artefact-free imaging. Thus, we utilise Phosphorescence Lifetime Imaging Microscopy (PLIM) to visualise G-quadruplexes in live and fixed cells using this novel PLIM probe.
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Journal articleMatthews PM, Allen NE, Debette S, et al., 2026, , Nat Rev Neurol
UK Biobank is the world's most comprehensive longitudinal population-based data and biosample resource. Twenty years after UK Biobank was first established, the incidence of dementia among participants is rising and is set to increase rapidly over the next 5-10 years, creating a distinct opportunity for studies of dementia risk and onset. In addition to extensive clinical phenotyping of >500,000 volunteers from across the UK at recruitment and at follow-up time points, UK Biobank includes data from serial lifestyle questionnaires, cognitive testing, multimodal imaging, accelerometry, genomics and other omics that are linked to individual health, cancer and death records. In this Perspective, we discuss how the use of UK Biobank data has enabled the discovery of new interactions between systemic and brain health and illustrate how these data can be used to characterize and identify risk factors, support mechanistic hypotheses and identify new biomarkers that predict the onset and course of dementia and related disorders. We also consider future developments of UK Biobank, including the UK Biobank Brain Health Study, which will build on and leverage the increasing incidence of dementias to advance understanding of these conditions.
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Journal articleBalkwill FR, Laumont CM, Burdett N, et al., 2026, , Nat Rev Cancer
Approximately 80% of deaths from ovarian cancer are due to high-grade serous carcinoma (HGSC), which has the highest proportion of BRCA1 or BRCA2 (BRCA1/BRCA2) mutations of any cancer type and is a highly chromosomally unstable disease. Despite the introduction of targeted therapies benefitting some patients with HGSC as well as surgical advances, only 50% of patients will survive more than 5 years, and just 30% of patients who present with advanced disease without BRCA1/BRCA2 mutations will survive this long. This Expert Recommendation is based on discussions among emerging and leading ovarian cancer researchers at the 15th Helene Harris Memorial Trust International Forum on ovarian cancer hosted by Ovarian Cancer Action in October 2024. The meeting considered advances in HGSC research and treatment made over the last decade, current challenges, emerging technologies in prevention, early detection, and treatment, and research priorities for the years ahead.
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