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 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 articleChen S-Y, Bennett J, Navaratnam N, et al., 2026,
Binding of 14-3-3 stabilises recombinant AMPKγ2-containing complexes.
, Biochem J, Vol: 483, Pages: 621-637AMP-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.
-
Journal articlePierret ACS, Patel AH, Daniels E, et al., 2026,
Kisspeptin as a test of hypothalamic dysfunction in pubertal and reproductive disorders
, Andrology, Vol: 14, Pages: 1002-1016, ISSN: 2047-2919The 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.
-
Journal articleKalafateli M, Sena Aydin B, Polat B, et al., 2026,
Metabolic-associated steatotic liver disease (MASLD): how I evolved my approach to diagnosis and staging
, Frontline Gastroenterology, Vol: 17, Pages: 250-261, ISSN: 2041-4145Metabolic 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.
-
Journal articleIorra F, Jayakar T, Yee M, et al., 2026,
Effects of GLP-1 Receptor Agonists on Muscle Mass, Strength, and Quality in MASLD: A Systematic Review.
, Liver Int, Vol: 46BACKGROUND AND AIMS: GLP-1 receptor agonists (GLP-1RAs) promote significant weight loss, but their impact on muscle mass, strength, and quality in metabolic dysfunction-associated steatotic liver disease (MASLD), a condition prone to muscle impairment, remains uncertain. METHODS: We conducted a systematic review of MEDLINE/PubMed, Embase, and the Cochrane Library up to 2 December 2025. Interventional and observational studies assessing GLP-1RA therapy and muscle-related outcomes in adults with MASLD were included. Muscle mass was assessed by computed tomography or magnetic resonance imaging, dual-energy X-ray absorptiometry, or bioelectrical impedance analysis; lean mass and fat-free mass were considered proxies. Muscle strength was evaluated using handgrip strength (HGS) or sit-to-stand (STS) tests. Muscle quality was assessed by imaging-based quantification of intramuscular fat infiltration (myosteatosis) or functionally based on performance relative to muscle mass. Results were synthesised narratively. RESULTS: Twelve studies were included (n = 810). Eleven assessed muscle mass (n = 785) across different GLP-1RA regimens and treatment durations (12-52 weeks). Findings suggested relative preservation of muscle mass, with modest reductions generally proportional to overall weight loss. Muscle strength was evaluated in three studies (n = 477), with no evidence of deterioration in HGS or STS performance despite meaningful weight loss. Muscle quality was assessed in four studies (n = 139) using imaging or functional metrics, with results suggesting preserved or improved muscle quality. Evidence was limited by small sample sizes and heterogeneous assessment methods. CONCLUSION: Current evidence suggests that GLP-1RA therapy is not associated with clinically meaningful loss of muscle mass or strength in adults with MASLD, with early data indicating possible improvements in muscle quality.
-
Journal articleWallace DV, Hossny EM, Levin M, et al., 2026,
Anaphylaxis Guidelines.
, Immunol Allergy Clin North Am, Vol: 46, Pages: 233-256This 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.
-
Journal articleGiang S, Dall'Era MA, Jones RB, et al., 2026,
Systematic Review of Trial Design and End Points in Lupus Nephritis.
, Kidney Int Rep, Vol: 11INTRODUCTION: Advances in our understanding of immune dysregulation in lupus nephritis (LN) are driving a surge in the development of targeted pharmaceutical agents for a disease that continues to carry a high rate of morbidity and mortality. Although meaningful progress is being made in the management of LN, the substantial heterogeneity in critical elements of trial design and reporting that exists across contemporary LN trials hampers our ability to fairly compare the efficacy of new therapies. METHODS: In this review, we comprehensively summarized and compared end points, various aspects of methodology (including glucocorticoid usage and eligibility criteria), actual trial population, and results reporting across studies published in the last 2 decades. We assessed 15 phase 2/3, interventional, randomized controlled trials (RCTs), of which 4 demonstrated the superiority of the investigational agent over standard therapy. RESULTS: Emerging themes comprise the inclusion of participants with high median baseline kidney function (median of the average baseline estimated glomerular filtration rate (eGFR) was 95 ml/min per 1.73 m2), differences in definitions of active disease, high variability in kidney function, and glucocorticoid-based definitions of treatment response. CONCLUSION: Based on the findings of this review, we suggest a set of expert-posited guidelines to help in standardizing future studies in LN.
-
Journal articleFaghy MA, Wüst RCI, Altmann DM, et al., 2026,
Current status and future perspectives on the mechanistic and pathophysiological understanding of long COVID.
, Commun Med (Lond), Vol: 6BACKGROUND: Viral and infectious illnesses can exert profound and enduring effects on population health and well-being. In the aftermath of SARS-CoV-2 infection, post-acute sequelae, collectively referred to as Long COVID, have emerged as a major global health challenge, affecting more than 400 million people and contributing to estimated annual economic costs exceeding $1 trillion. SCOPE OF THE REVIEW: Long COVID encompasses a wide and heterogeneous spectrum of debilitating symptoms, including cognitive dysfunction, sleep disturbances, severe fatigue, and post-exertional malaise. Despite its substantial burden, fundamental uncertainties remain regarding its underlying pathophysiology, the development of robust diagnostic criteria, and the identification of effective therapeutic options. KEY INSIGHTS: This review synthesises current evidence on the biological mechanisms thought to contribute to Long COVID, spanning immune dysregulation, viral persistence, autonomic dysfunction, microvascular pathology, and other emerging hypotheses. We examine advances and limitations in contemporary diagnostic approaches and critically appraise existing treatment strategies, highlighting inconsistencies and gaps that hinder clinical consensus. IMPLICATIONS: By integrating interdisciplinary insights, this review underscores the urgent need for mechanistic clarity, validated diagnostic frameworks, and rigorously evaluated treatment pathways. Addressing these gaps will be essential to developing effective, evidence-based management strategies and mitigating the long-term impact of Long COVID on global health.
-
Journal articleMatthews PM, Allen NE, Debette S, et al., 2026,
Author Correction: UK Biobank at 20 - a growing, global resource for dementia research.
, Nat Rev Neurol
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.