The Immune Environment in Colorectal Adenoma: A Systematic ReviewSilinskaite, Valciukiene, Jakubauskas
et alBiomedicines (2025) 13 (3)
Abstract: Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.
Safety and efficacy of atorvastatin for rebleeding in cerebral cavernous malformations (AT CASH EPOC): a phase 1/2a, randomised placebo-controlled trialAwad, Alcazar-Felix, Stadnik
et alLancet Neurol (2025) 24 (4), 295-304
Abstract: Cerebral cavernous malformations (CCMs) carry a high risk of rebleeding after symptomatic haemorrhage, with serious clinical sequelae. Atorvastatin was shown to prevent CCM growth and bleeding in animal models. We aimed to assess the safety and efficacy of atorvastatin on rebleeding in patients with CCMs after a symptomatic haemorrhage.We did a phase 1/2a randomised trial at the University of Chicago's CCM Center of Excellence. Patients aged 18-80 years with untreated CCMs who had had symptomatic bleeding from a CCM lesion within the previous year were eligible. Patients were randomly allocated (1:1) to oral atorvastatin (80 mg daily for 2 years) or matching placebo. Investigators, clinical staff, and participants were masked to the assigned treatment. The primary efficacy outcome was the percentage change in mean lesional iron deposition per year, measured by quantitative susceptibility mapping (QSM) on MRI and averaged over 2 years; a decrease would signal potential benefit and an increase a safety concern. The primary efficacy outcome was analysed in the modified intention-to-treat cohort, including patients with at least one annual paired QSM assessment. Safety outcomes included rates of bleeds and serious adverse events necessitating drug discontinuation. This trial is registered at ClinicalTrials.gov (NCT02603328) and is completed.Between July 25, 2018, and July 22, 2022, 326 patients were assessed for eligibility, and 80 patients were allocated either atorvastatin (n=41) or placebo (n=39). 29 (36%) patients were male and 51 (64%) were female. 64 (80%) patients (33 in the atorvastatin group and 31 in the placebo group) had at least one annual paired QSM assessment and were included in the modified intention-to-treat analyses. The mean annual percentage change in lesional QSM was 10·88 (SE 7·29) with atorvastatin versus 12·09 (SE 7·54) with placebo (treatment effect -1·22, 95% CI -22·25 to 19·81; p=0·91). Symptomatic haemorrhage was reported in six patients assigned atorvastatin and seven patients assigned placebo (relative risk 0·81, 95% CI 0·31 to 2·13). No patients had a serious adverse event requiring drug discontinuation and no deaths were recorded.For people with symptomatic haemorrhage caused by CCMs, atorvastatin did not affect the mean change in lesional iron deposition on brain MRI over 2 years when compared with placebo. Atorvastatin was well tolerated and no safety concerns were noted. The study provides a useful framework for biomarker driven drug assessment in a rare disease.US National Institutes of Health.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Dihydromyricetin alleviates imiquimod-induced psoriasiform inflammation by inhibiting M1 macrophage polarizationLi, Zhou, Mao
et alArch Dermatol Res (2025) 317 (1), 410
Abstract: Dihydromyricetin (DMY), a flavonoid, belongs to a class of natural compounds and possesses anti-inflammatory properties. The objective of this research is to investigate the effects and mechanism of DMY in mice induced by imiquimod (IMQ). Here, DMY ointment was topically applied to evaluate the effect of DMY on psoriasis, while the results showed DMY improved clinical phenotype of IMQ-induced psoriasiform dermatitis. Histological evaluation revealed decreases in keratinocyte hyperplasia and immune cell infiltration in mice after DMY administration. Besides, DMY treatment could attenuate psoriasiform inflammation as showed in the decreased expression of inflammation mediators such as IL-17a, IL-23a, TNF-α, IL-6, IL-1β, IL-12a, CXCL2, and S100A8 in the skin of mice. Mechanistically, DMY reduced the polarization of macrophages towards the pro-inflammatory M1 phenotype by inhibiting the TLR4/NF-κB pathway, importantly, which subsequently regulated the differentiation of T helper (Th) 1 and Th17 cell subsets, leading to the relief of immune inflammatory response in psoriasis. In conclusion, the research reveals that DMY markedly attenuated IMQ-induced psoriasis in mice and provides that DMY have great potential for treatment of psoriasis.© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Selective and Potent Molecular Glue Degraders for NIMA-Related Kinase 7Chen, Huang, Wen
et alAngew Chem Int Ed Engl (2025) 64 (12), e202500169
Abstract: Molecular glue degraders (MGDs) represent a promising strategy for targeted protein degradation within cells. While chemoproteomics has unveiled hundreds of potential MGD targets, very few proteins are degraded by highly selective and potent MGDs. Here, we developed a novel glutarimide analog with a tetrahydroimidazo[1,2-a]pyrazine scaffold that exhibited strong NIMA-related kinase 7 (NEK7) degradation potential. Further optimization led to the identification of LC-04-045 as a leading NEK7 MGD candidate, demonstrating potent activity with a half-maximal degradation (DC50) of 7 nM and a maximum degradation (Dmax) of 90 % in MOLT-4 cells. Notably, LC-04-045 displayed high selectivity for NEK7 across the proteome. Mechanistic studies indicated that the degradation was mediated by the ubiquitin-proteasome system (UPS) and relied on the glycine 57 (G57)-containing degron motif in NEK7. Additionally, two amino acids adjacent to the degron motif were found to be crucial for modulating the compound's selectivity and potency, underscoring the significance of neighbouring residues in MGD design. Moreover, LC-04-045 effectively inhibited secretion of the downstream cytokines, including IL-1β and IL-18, highlighting the potential therapeutic applications of NEK7 MGDs in treating inflammatory diseases.© 2025 Wiley-VCH GmbH.
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