Feed aggregator

Biomimetics (Basel). 2025 May 8;10(5):297. doi: 10.3390/biomimetics10050297.

ABSTRACT

This study investigates how different levels of extrusion pressure during 3D printing affect the cell viability of human bronchial epithelial (HBE) cells embedded in printed samples. In this study, samples were printed at three levels of extrusion pressure. The cell viability was assessed through live/dead staining via microscopic imaging. The results show that increasing the extrusion pressure from 50 to 100 kPa led to a higher degree of cell death. These results demonstrate how the extrusion pressure affects the viability of HBE cells and provide a basis for future studies on pressure-induced responses in respiratory tissues.

PMID:40422127 | DOI:10.3390/biomimetics10050297

Nat Commun. 2025 May 21;16(1):4726. doi: 10.1038/s41467-025-59826-8.

ABSTRACT

The upsurge of mpox in Africa and the recent global outbreak have stimulated the development of new vaccines and therapeutics. We describe the construction of virus-like particle (VLP) vaccines in which modified M1, A35 and B6 proteins from monkeypox virus (MPXV) clade Ia are conjugated individually or together to a scaffold that accommodates up to 60 ligands using the SpyTag/SpyCatcher nanoparticle system. Immunisation of female mice with VLPs induces higher anti-MPXV and anti-vaccinia virus (VACV) neutralizing antibodies than their soluble protein (SP) counterparts or modified VACV Ankara (MVA). Vaccination with individual single protein VLPs provides partial protection against lethal respiratory infections with VACV or MPXV clade IIa, whereas combinations or a chimeric VLP with all three antigens provide complete protection that is superior to SPs. Additionally, the VLP vaccine reduces the replication and spread of the virus at intranasal and intrarectal sites of inoculation. VLPs induce higher neutralizing activity than the Jynneos vaccine in rhesus macaques, and the VLP-induced antiserum provides better protection against MPXV and VACV than the Jynneos-induced antiserum when passively transferred to female mice. These data demonstrate that an mpox VLP vaccine derived from three MPXV clade Ia proteins protects against clade IIa MPXV and VACV, indicating cross-reactivity for orthopoxviruses.

PMID:40399314 | DOI:10.1038/s41467-025-59826-8

Nat Commun. 2025 May 21;16(1):4726. doi: 10.1038/s41467-025-59826-8.

ABSTRACT

The upsurge of mpox in Africa and the recent global outbreak have stimulated the development of new vaccines and therapeutics. We describe the construction of virus-like particle (VLP) vaccines in which modified M1, A35 and B6 proteins from monkeypox virus (MPXV) clade Ia are conjugated individually or together to a scaffold that accommodates up to 60 ligands using the SpyTag/SpyCatcher nanoparticle system. Immunisation of female mice with VLPs induces higher anti-MPXV and anti-vaccinia virus (VACV) neutralizing antibodies than their soluble protein (SP) counterparts or modified VACV Ankara (MVA). Vaccination with individual single protein VLPs provides partial protection against lethal respiratory infections with VACV or MPXV clade IIa, whereas combinations or a chimeric VLP with all three antigens provide complete protection that is superior to SPs. Additionally, the VLP vaccine reduces the replication and spread of the virus at intranasal and intrarectal sites of inoculation. VLPs induce higher neutralizing activity than the Jynneos vaccine in rhesus macaques, and the VLP-induced antiserum provides better protection against MPXV and VACV than the Jynneos-induced antiserum when passively transferred to female mice. These data demonstrate that an mpox VLP vaccine derived from three MPXV clade Ia proteins protects against clade IIa MPXV and VACV, indicating cross-reactivity for orthopoxviruses.

PMID:40399314 | DOI:10.1038/s41467-025-59826-8

Semin Musculoskelet Radiol. 2025 Jun;29(3):403-416. doi: 10.1055/s-0045-1806794. Epub 2025 May 20.

ABSTRACT

The menisci play a crucial role in knee stability, load distribution, and shock absorption. Their anatomical structure is linked to the way they perform. Meniscal injuries are common in both athletic and nonathletic populations, accounting for > 60% of all reported knee injuries, making them the most common type of knee injury resulting from acute trauma or degenerative changes. Meniscal tears typically result from a combination of axial loading and rotational force. The medial meniscus is the most affected. Tears can be classified based on their location, pattern, and stability, influencing treatment decisions. The three patterns are horizontal tear (simple or complex with a flap), vertical or longitudinal tear (simple, bucket-handle, or specific case meniscal ramp tear), and radial tear (simple, parrot beak, and specific case meniscal root tears). Some diagnostic pitfalls are anatomical variants, ligamentous or tendinous structures, or variations in signal or meniscal shape.

PMID:40393499 | DOI:10.1055/s-0045-1806794

Semin Musculoskelet Radiol. 2025 Jun;29(3):390-402. doi: 10.1055/s-0045-1806795. Epub 2025 May 20.

ABSTRACT

Anterior cruciate ligament tears represent a prevalent injury in sports that involves rotational movements and rapid changes in direction, such as pivot-contact sports. The anterior cruciate ligament serves as the primary stabilizer of the knee, preventing anterior tibial translation and medial tibial rotation. Although clinical examination is essential for diagnosis, magnetic resonance imaging plays a crucial role in confirming complete tears and evaluating associated injuries, particularly meniscal injuries. Diagnosis relies on both direct and secondary signs that are instrumental in assessing knee laxity and stability. Despite advancements in imaging techniques, challenges persist in using magnetic resonance imaging to distinguish between complete and partial tears, evaluate knee instability, and determine the potential for anterior cruciate ligament healing.

PMID:40393498 | DOI:10.1055/s-0045-1806795

Sci Signal. 2025 May 20;18(887):eado7543. doi: 10.1126/scisignal.ado7543. Epub 2025 May 20.

ABSTRACT

G protein-coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 Gα proteins that can couple to GPCRs, variation in a single Gα can affect the function of numerous receptors. Here, we investigated two mutant forms of Gαs (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. Gαs is encoded by an imprinted gene, resulting in the mutant form of Gαs being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR-G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by Gαs mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired Gαs interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric Gs. This indicates that different signal transduction steps can be altered by specific Gαs mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts.

PMID:40392940 | DOI:10.1126/scisignal.ado7543

Sci Signal. 2025 May 20;18(887):eado7543. doi: 10.1126/scisignal.ado7543. Epub 2025 May 20.

ABSTRACT

G protein-coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 Gα proteins that can couple to GPCRs, variation in a single Gα can affect the function of numerous receptors. Here, we investigated two mutant forms of Gαs (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. Gαs is encoded by an imprinted gene, resulting in the mutant form of Gαs being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR-G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by Gαs mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired Gαs interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric Gs. This indicates that different signal transduction steps can be altered by specific Gαs mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts.

PMID:40392940 | DOI:10.1126/scisignal.ado7543

Chem Sci. 2025 May 6. doi: 10.1039/d5sc02286j. Online ahead of print.

ABSTRACT

Protein-antibody conjugates represent major advancements in targeted therapeutics. However, platforms enabling 'off-the-shelf' antibody conjugation are seldom reported. The SpyTag/SpyCatcher system, known for its stable isopeptide bond formation, is widely used to engineer protein architectures and study protein folding. This work introduces the fusion of SpyCatcher with native antibodies using cysteine-reactive tetra-divinylpyrimidine (TetraDVP)-SpyTag linkers. This platform allows for the rapid and stable conjugation of a native antibody with SpyCatcher proteins. As a proof of concept, the HER2-targeting antibody trastuzumab was conjugated to different SpyCatcher proteins using a TetraDVP-SpyTag linker, producing robust conjugates that retained specific binding to HER2-positive cells with excellent conversion rates. To demonstrate the platform's broader applicability, the TetraDVP-SpyTag linker was successfully conjugated to additional native IgG1 and IgG4 antibodies (durvalumab, brentuximab, cetuximab, and gemtuzumab) with similarly high efficiency as trastuzumab. Moreover, a scalable solid-phase synthesis of TetraDVP linkers has been developed, achieving high yields and purity. This innovative platform enables precise, single-step antibody bioconjugation, offering strong potential for protein-antibody conjugate synthesis. With applications across therapeutics and diagnostics, this method advances antibody-based drug development.

PMID:40386161 | PMC:PMC12080404 | DOI:10.1039/d5sc02286j

Chem Sci. 2025 May 6. doi: 10.1039/d5sc02286j. Online ahead of print.

ABSTRACT

Protein-antibody conjugates represent major advancements in targeted therapeutics. However, platforms enabling 'off-the-shelf' antibody conjugation are seldom reported. The SpyTag/SpyCatcher system, known for its stable isopeptide bond formation, is widely used to engineer protein architectures and study protein folding. This work introduces the fusion of SpyCatcher with native antibodies using cysteine-reactive tetra-divinylpyrimidine (TetraDVP)-SpyTag linkers. This platform allows for the rapid and stable conjugation of a native antibody with SpyCatcher proteins. As a proof of concept, the HER2-targeting antibody trastuzumab was conjugated to different SpyCatcher proteins using a TetraDVP-SpyTag linker, producing robust conjugates that retained specific binding to HER2-positive cells with excellent conversion rates. To demonstrate the platform's broader applicability, the TetraDVP-SpyTag linker was successfully conjugated to additional native IgG1 and IgG4 antibodies (durvalumab, brentuximab, cetuximab, and gemtuzumab) with similarly high efficiency as trastuzumab. Moreover, a scalable solid-phase synthesis of TetraDVP linkers has been developed, achieving high yields and purity. This innovative platform enables precise, single-step antibody bioconjugation, offering strong potential for protein-antibody conjugate synthesis. With applications across therapeutics and diagnostics, this method advances antibody-based drug development.

PMID:40386161 | PMC:PMC12080404 | DOI:10.1039/d5sc02286j

Nano Lett. 2025 May 16. doi: 10.1021/acs.nanolett.5c01101. Online ahead of print.

ABSTRACT

The Casimir force dominates interactions between solid objects at sub-micrometer distances and typically limits the smallest distance between micromechanical devices before failure. Here, we experimentally circumvent this limitation by controlling the Casimir force with engineered 3D nanostructures. Using our recently developed method to align and measure the force between two microscale objects on the nanoscale, we characterized the force gradient between spheres and circular pillars, hollow cylinders, and periodic pillar arrays. We demonstrate that the force behavior can be dramatically modified in these geometries, resulting in a suppression of the Casimir force by 10× for a single pillar. We found agreement between theory and experiment, even when the size of the objects was comparable to the surface-to-surface separation (i.e., within a factor of ∼3). We anticipate that our results will impact the design of future micro- and nanoscale actuators, optomechanical devices with increased sensitivities and reduced stiction, and advanced bio-inspired adhesives.

PMID:40378088 | DOI:10.1021/acs.nanolett.5c01101

Chem Sci. 2025 May 5. doi: 10.1039/d5sc00903k. Online ahead of print.

ABSTRACT

The cell's ability to rapidly partition biomolecules into biomolecular condensates is linked to a diverse range of cellular functions. Understanding how the structural attributes of biomolecular condensates are linked with their biological roles can be facilitated by the development of synthetic condensate systems that can be manipulated in a controllable and predictable way. Here, we design and characterise a tuneable synthetic biomolecular condensate platform fusing modular consensus-designed tetratricopeptide repeat (CTPR) proteins to intrinsically-disordered domains. Trends between the CTPR structural attributes and condensate propensity were recapitulated across different experimental conditions and by in silico modelling, demonstrating that the CTPR domain can systematically affect the condensates in a predictable manner. Moreover, we show that incorporating short binding motifs into the CTPR domain results in specific target-protein recruitment into the condensates. Our model system can be rationally designed in a versatile manner to both tune condensate propensity and endow the condensates with new functions.

PMID:40375868 | PMC:PMC12076082 | DOI:10.1039/d5sc00903k

Chem Sci. 2025 May 5. doi: 10.1039/d5sc00903k. Online ahead of print.

ABSTRACT

The cell's ability to rapidly partition biomolecules into biomolecular condensates is linked to a diverse range of cellular functions. Understanding how the structural attributes of biomolecular condensates are linked with their biological roles can be facilitated by the development of synthetic condensate systems that can be manipulated in a controllable and predictable way. Here, we design and characterise a tuneable synthetic biomolecular condensate platform fusing modular consensus-designed tetratricopeptide repeat (CTPR) proteins to intrinsically-disordered domains. Trends between the CTPR structural attributes and condensate propensity were recapitulated across different experimental conditions and by in silico modelling, demonstrating that the CTPR domain can systematically affect the condensates in a predictable manner. Moreover, we show that incorporating short binding motifs into the CTPR domain results in specific target-protein recruitment into the condensates. Our model system can be rationally designed in a versatile manner to both tune condensate propensity and endow the condensates with new functions.

PMID:40375868 | PMC:PMC12076082 | DOI:10.1039/d5sc00903k

Protein Sci. 2025 Jun;34(6):e70150. doi: 10.1002/pro.70150.

ABSTRACT

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

PMID:40371781 | DOI:10.1002/pro.70150

Protein Sci. 2025 Jun;34(6):e70150. doi: 10.1002/pro.70150.

ABSTRACT

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

PMID:40371781 | DOI:10.1002/pro.70150

J Am Chem Soc. 2025 May 12. doi: 10.1021/jacs.5c00567. Online ahead of print.

ABSTRACT

This study investigates the roles of ethylene and ethylidyne in the surface chemistry of N-methylaniline (NMA) on Pt(111). Using X-ray photoelectron spectroscopy, temperature-programmed desorption, and density functional theory calculations, we demonstrate that ethylidyne is not merely a passive spectator species but actively contributes to hydroamination. It facilitates C-N bond formation by transferring a methyl group to NMA, leading to the formation of N,N-dimethylaniline. Additionally, it stabilizes reaction intermediates and suppresses the decomposition of NMA. This works demonstrates, in contrast to the widely accepted notion, that ethylidyne is not just an inert spectator species; rather, it plays a dual role as both an active reaction partner and a stabilizer. In addition, the coadsorption of ethylene on an NMA-precovered surface shows a side reaction of ethylene with the decomposition products of NMA.

PMID:40353685 | DOI:10.1021/jacs.5c00567

Spec Care Dentist. 2025 May-Jun;45(3):e70041. doi: 10.1111/scd.70041.

ABSTRACT

INTRODUCTION: Poor oral health (OH) can led to severe general health issues, including respiratory infections and malnutrition, impacting the quality of life. In Malaysia, high prevalence of oral diseases including dental caries among individuals with disabilities (IWDs) has been reported, indicating a possible gap in the current system. This study aimed to analyze caries experience using DMFT index of IWDs in community-based rehabilitation (CBR) centers across Selangor, Malaysia.

METHODS: A CBR centers-based cross-sectional study was conducted on IWDs or CBR trainees in the period between August 2022 and December 2023. Recruitments of the study participants were done via census sampling method, involving all the trainees within the specific centers. Data collection was done using the World Health Organization oral health survey tool (WHO, 2013) and analyzed using SPSS 24.

RESULTS: Two hundred and twenty-six students with the age range of 2-47 years old were included in the study. Clinical examination of CBR trainees revealed (1) the mean DMFT scores were low for primary dentition (2.02), moderate for both mixed (3.86), and permanent dentitions (4.17); (2) prevalence of caries among those with primary, mixed, and permanent dentitions as 44.44%, 74.4%, and 74.80%, respectively.

CONCLUSIONS: Trainees with primary dentition had a low prevalence of dental caries and mean DMFT score, while those with mixed and permanent dentition exhibited moderate levels. A statistically significant association was observed between the total DMFT scores for participants with primary dentition with both gender and disability types.

PMID:40353331 | DOI:10.1111/scd.70041

Lancet Oncol. 2025 May 7:S1470-2045(25)00156-1. doi: 10.1016/S1470-2045(25)00156-1. Online ahead of print.

ABSTRACT

BACKGROUND: Carriers of BRCA1 and BRCA2 pathogenic variants are at elevated risk of developing breast and ovarian cancers. To mitigate ovarian cancer risk, bilateral salpingo-oophorectomy (BSO) is commonly recommended for unaffected carriers and those with personal breast cancer history. Assessing BSO's long-term health outcomes in carriers with previous breast cancer history is essential. This study aims to examine the association between BSO and long-term health outcomes in individuals carrying pathogenic variants in BRCA1 and BRCA2 and with personal history of breast cancer.

METHODS: Data from the National Cancer Registration Dataset (NCRD) were linked with data from genetic testing laboratories to identify carriers of BRCA1 and BRCA2 pathogenic variants affected by breast cancer using pseudonymised patient identifiers. Further linkage to the Hospital Episode Statistics-Admitted Patient Care (HES-APC) dataset identified patients who had undergone BSO. Women aged 20-75 years, with a diagnosis of breast cancer as their first primary malignancy in 1995-2019 were eligible. Long-term health outcomes were identified from HES-APC and NCRD. Missing data were imputed using multivariate imputations by chained equations. Multivariable Cox regression was used to examine the associations with mortality (all-cause mortality, breast cancer-specific mortality, and non-breast cancer-specific mortality), second non-breast cancer, cardiovascular diseases, ischaemic heart disease, cerebrovascular diseases, contralateral breast cancer, and depression. Analyses were adjusted for age at diagnosis, diagnosis year, ethnicity, deprivation index, tumour characteristics, Charlson comorbidity index, cancer treatment, and second cancer diagnosis before the start of follow-up.

FINDINGS: We included 1674 BRCA1, 1740 BRCA2, and nine BRCA1 and BRCA2 carriers who were diagnosed with breast cancer between 1995 and 2019, with median follow-up time of 5·5 years (IQR 3·4-8·2). The study population (n=3423) consisted of 3002 (88·7%) White, 170 (5·0%) Asian, 59 (1·7%) Black, 26 (0·8%) mixed, and 74 (2·2%) other ethnic groups, and 92 (2·7%) had missing ethnicity. The uptake of BSO was significantly lower among Black women (odds ratio [OR] vs White women 0·48, 95% CI 0·34-0·67), and Asian women (0·47, 0·27-0·82). BSO uptake was higher in women living in the least socioeconomically deprived areas (OR vs most deprived 1·38, 95% CI [1·10-1·72]). BSO was associated with a reduced risk of all-cause mortality for both BRCA1 and BRCA2 pathogenic variant carriers (HR 0·52, 95% CI 0·41-0·64) and reduced breast cancer-specific mortality (BRCA1: HR 0·62, 95% CI 0·42-0·92 and BRCA2: 0·48, 0·34-0·68). It was also associated with a reduced risk of second non-breast cancer in the combined BRCA1 and BRCA2 sample (HR 0·59, 95% CI 0·37-0·94). There BSO was not associated with increased risk of cardiovascular diseases (HR 0·73, 95% CI 0·53-1·01), ischaemic heart disease (1·04, 0·48-2·26), cerebrovascular disease (0·32, 0·11-0·90), non-breast cancer specific mortality (0·72, 0·45-1·16), contralateral breast cancer (1·18, 0·64-2·16), or depression (0·94, 0·62-1·42).

INTERPRETATION: The evidence supports offering BSO to BRCA1 and BRCA2 pathogenic variant carrriers with a personal history of breast cancer, as they appear to benefit from having the procedure, without evidence of an increased risk of adverse long-term health outcomes.

FUNDING: Cancer Research UK.

PMID:40347974 | DOI:10.1016/S1470-2045(25)00156-1

J Vasc Surg Venous Lymphat Disord. 2025 May 5:102255. doi: 10.1016/j.jvsv.2025.102255. Online ahead of print.

ABSTRACT

OBJECTIVE: Mechanochemical ablation is a feasible endovenous nonthermal, nontumescent treatment method for saphenous vein insufficiency.1,2,3 Nevertheless, the ideal approach to managing varicose veins following intervention of the saphenous trunk remains ambiguous.1 Treatment of varicose veins can be administered either simultaneously or in a staged manner.1 The aim of this three-year follow-up study was to present the midterm outcomes of a randomized controlled trial, comparing concomitant and staged treatment of tributaries.

METHODS: Venous outpatient clinic patients with unilateral CEAP (clinical, etiological, anatomical, pathophysiological) C2-4 venous disease were enrolled in a randomized controlled trial during 2016-2017 at Helsinki University Hospital. After eligibility assessment of 1149 patients, 85 met the inclusion criteria: age of 20-70 years, ultrasound-verified refluxing above-knee great saphenous vein with a diameter of 5-10 millimeters, written consent from patients and not having deep venous reflux, peripheral artery disease, pregnancy, lymphoedema, body mass index > 40 kg/m2, allergy to the sclerosant, a history of deep vein thrombosis or any form of coagulopathy.

PARTICIPANTS: Were randomized, in a 1:1 ratio, to receive either staged tributary treatment with foam sclerotherapy at three months, if required (Group 1), or concomitant phlebectomies (Group 2), adjunct to mechanochemical ablation of the great saphenous trunk. All patients were invited to attend a three-year follow-up, during which the initially treated leg was assessed with duplex ultrasound. The primary outcome was reintervention rate during follow-up. Secondary outcomes comprised presence of above-knee great saphenous vein reflux, patient satisfaction, status of the great saphenous vein, number of varicose veins, and symptoms at follow-up.

RESULTS: During follow-up, 11.4 % (n=5/44) [95% CI, 0.02-0.21] in Group 1 and 4.9 % (n=2/41) [95% CI, -0.02-0.11] in Group 2 was in need of additional treatment (Group 1 vs Group 2 OR=2.5 [95% CI 0.46-13.67], P=0.435). The treatment groups did not elicit statistically significant variances in above-knee great saphenous vein reflux (P=0.603), disease-specific and health-related quality of life (P=0.238 and P=0.255 respectively), status of the great saphenous vein (P=0.112), or symptoms. However, noninferiority analysis suggests the staged approach to be inferior to the concomitant approach. Furthermore, Group 1 exhibited more varicosities at three years compared to Group 2, but this did not cause differences in the extent of symptoms or overall patient satisfaction.

CONCLUSION: Staged treatment of tributaries in C2-4 venous disease provides acceptable midterm outcomes compared to simultaneous treatment. However, its potential inferiority should be taken into consideration when prioritizing durable treatment outcomes in the long term.

PMID:40335021 | DOI:10.1016/j.jvsv.2025.102255

EMBO J. 2025 May 6. doi: 10.1038/s44318-025-00447-8. Online ahead of print.

ABSTRACT

The identification of tumour-specific protein-protein interactions remains a challenge for the development of targeted cancer therapies. In this study we describe our approach for the identification of triple negative breast cancer (TNBC)-specific protein-protein interactions focusing on the oncogene BCL11A. We used a proteomic approach to identify the BCL11A protein networks in TNBC and compared it to its network in B-cells, a cell type in which BCL11A plays crucial roles. This approach identified the chromatin remodeller CHD8 as a TNBC-specific interaction partner of BCL11A. We show that CHD8 also plays a key role in TNBC pathogenesis, with detailed multi-omics analysis revealing that BCL11A and CHD8 co-regulate several targets and synergise to drive tumour development and progression. Using a battery of biophysical assays, we confirm that the BCL11A-CHD8 interaction is direct and identify chemical fragments that disrupt this interaction and affect downstream targets, decreasing proliferation in 3D colony assays. Our study provides a proof-of-principle approach for investigating tumour-specific protein-protein interactions and identifies lead chemical compounds that could be developed into novel therapeutics for TNBC.

PMID:40328966 | DOI:10.1038/s44318-025-00447-8

EMBO J. 2025 May 6. doi: 10.1038/s44318-025-00447-8. Online ahead of print.

ABSTRACT

The identification of tumour-specific protein-protein interactions remains a challenge for the development of targeted cancer therapies. In this study we describe our approach for the identification of triple negative breast cancer (TNBC)-specific protein-protein interactions focusing on the oncogene BCL11A. We used a proteomic approach to identify the BCL11A protein networks in TNBC and compared it to its network in B-cells, a cell type in which BCL11A plays crucial roles. This approach identified the chromatin remodeller CHD8 as a TNBC-specific interaction partner of BCL11A. We show that CHD8 also plays a key role in TNBC pathogenesis, with detailed multi-omics analysis revealing that BCL11A and CHD8 co-regulate several targets and synergise to drive tumour development and progression. Using a battery of biophysical assays, we confirm that the BCL11A-CHD8 interaction is direct and identify chemical fragments that disrupt this interaction and affect downstream targets, decreasing proliferation in 3D colony assays. Our study provides a proof-of-principle approach for investigating tumour-specific protein-protein interactions and identifies lead chemical compounds that could be developed into novel therapeutics for TNBC.

PMID:40328966 | DOI:10.1038/s44318-025-00447-8