Gabriela O. Girón, Sergi Otero, Panagiota Efstathia Nikolaou, Sebastià Alcover, Lisaidy Ramos-Regalado, Carlos Zaragoza, Luca Liberale, María Borrell-Pages, Teresa Padró, Rosa Suades, Gemma Vilahur
Background
A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk.
Methods
Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach.
Results
Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk.
Conclusion
The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction.
{"title":"Atherogenic dyslipidaemia and residual cardiovascular risk: Understanding the link to heart disease","authors":"Gabriela O. Girón, Sergi Otero, Panagiota Efstathia Nikolaou, Sebastià Alcover, Lisaidy Ramos-Regalado, Carlos Zaragoza, Luca Liberale, María Borrell-Pages, Teresa Padró, Rosa Suades, Gemma Vilahur","doi":"10.1111/eci.70167","DOIUrl":"10.1111/eci.70167","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander Schmitt, Ibrahim Akin, Marielen Reinhardt, Noah Abel, Felix Lau, Jonas Dudda, Mohammad Abumayyaleh, Kathrin Weidner, Thomas Bertsch, Daniel Duerschmied, Michael Behnes, Tobias Schupp
Background
This study investigates the prognostic impact of albumin, the urea-to-albumin ratio (UAR), and albumin-to-creatinine ratio (ACR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), since hypoalbuminemia, renal disease and malnutrition often coincide with heart failure (HF).
Methods
Consecutive patients hospitalized with HFmrEF at one university medical centre were retrospectively included from 2016 to 2022. Patients were stratified into quartiles based on albumin, the UAR, and ACR. The primary endpoint was all-cause mortality at 30 months (median follow-up), key secondary endpoint was long-term HF-related rehospitalization.
Results
The study cohort comprised 2,061 patients with HFmrEF with a median albumin level of 32.4 g/L. Albumin levels, the UAR and ACR were predictive for the risk of long-term all-cause mortality, which was still observed after multivariable adjustment (albumin Q1 vs. Q4: HR = 2.260; 95% CI 1.623–3.148; p = .001 / UAR Q4 vs. Q1: HR = 1.507; 95% CI 1.071–2.119; p = .019/ACR Q1 vs. Q4: HR = 2.208; 95% CI 1.528–3.190; p = .001). However, neither albumin nor the UAR or ACR predicted the risk of HF-related rehospitalization (albumin Q1 vs. Q4: HR = 1.117; 95% CI .678–1.842; p = .664 / UAR Q4 vs. Q1: HR = 1.589; 95% CI .922–2.738; p = .095 / ACR Q1 vs. Q4: HR = 1.112; 95% CI .624–1.981; p = .720).
Conclusions
Hypoalbuminemia is common in hospitalized HFmrEF patients. Low albumin levels, ACRs, and elevated UARs independently predicted long-term all-cause mortality, but not HF-related rehospitalization. The UAR and ACR did not provide a clinically significant predictive advantage over albumin levels alone.
Trial Registration
ClinicalTrials.gov Identifier: NCT05603390 (date of registration: 10.10.2020)
背景：由于低白蛋白血症、肾脏疾病和营养不良常伴随心力衰竭（HF），本研究探讨了白蛋白、尿白蛋白比（UAR）和白蛋白与肌酐比（ACR）对心力衰竭伴轻度射血分数降低（HFmrEF）患者预后的影响。方法：回顾性纳入2016年至2022年在一所大学医疗中心连续住院的HFmrEF患者。根据白蛋白、UAR和ACR将患者分为四分位数。主要终点是30个月时的全因死亡率（中位随访），关键的次要终点是长期hf相关再住院。结果：研究队列包括2061例HFmrEF患者，中位白蛋白水平为32.4 g/L。白蛋白水平、UAR和ACR是长期全因死亡风险的预测指标，在多变量调整后仍可观察到(白蛋白Q1 vs. Q4: HR = 2.260; 95% CI 1.623-3.148; p =。001 / UAR Q4 vs. Q1: HR = 1.507；95% ci 1.071-2.119；p =。019/ACR Q1 vs. Q4: HR = 2.208；95% ci 1.528-3.190；p = .001)。然而，白蛋白、UAR或ACR均不能预测hf相关再住院的风险(白蛋白Q1 vs. Q4: HR = 1.117; 95% CI .678-1.842; p =。664 / UAR Q4 vs Q1: HR = 1.589；95% ci: 0.922 -2.738；p =。Q1 vs. Q4: HR = 1.112；95% ci为624-1.981；p = .720)。结论：低白蛋白血症在住院HFmrEF患者中很常见。低白蛋白水平、acr和uar升高独立预测长期全因死亡率，但不能预测hf相关的再住院。与单独的白蛋白水平相比，UAR和ACR没有提供临床显著的预测优势。试验注册：ClinicalTrials.gov标识符：NCT05603390（注册日期：10.10.2020）。
{"title":"Albumin, urea-to-albumin ratio, or the albumin-to-creatinine ratio to predict outcomes in heart failure with mildly reduced ejection fraction","authors":"Alexander Schmitt, Ibrahim Akin, Marielen Reinhardt, Noah Abel, Felix Lau, Jonas Dudda, Mohammad Abumayyaleh, Kathrin Weidner, Thomas Bertsch, Daniel Duerschmied, Michael Behnes, Tobias Schupp","doi":"10.1111/eci.70165","DOIUrl":"10.1111/eci.70165","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study investigates the prognostic impact of albumin, the urea-to-albumin ratio (UAR), and albumin-to-creatinine ratio (ACR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), since hypoalbuminemia, renal disease and malnutrition often coincide with heart failure (HF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Consecutive patients hospitalized with HFmrEF at one university medical centre were retrospectively included from 2016 to 2022. Patients were stratified into quartiles based on albumin, the UAR, and ACR. The primary endpoint was all-cause mortality at 30 months (median follow-up), key secondary endpoint was long-term HF-related rehospitalization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study cohort comprised 2,061 patients with HFmrEF with a median albumin level of 32.4 g/L. Albumin levels, the UAR and ACR were predictive for the risk of long-term all-cause mortality, which was still observed after multivariable adjustment (albumin Q1 vs. Q4: HR = 2.260; 95% CI 1.623–3.148; <i>p</i> = .001 / UAR Q4 vs. Q1: HR = 1.507; 95% CI 1.071–2.119; <i>p</i> = .019/ACR Q1 vs. Q4: HR = 2.208; 95% CI 1.528–3.190; <i>p</i> = .001). However, neither albumin nor the UAR or ACR predicted the risk of HF-related rehospitalization (albumin Q1 vs. Q4: HR = 1.117; 95% CI .678–1.842; <i>p</i> = .664 / UAR Q4 vs. Q1: HR = 1.589; 95% CI .922–2.738; <i>p</i> = .095 / ACR Q1 vs. Q4: HR = 1.112; 95% CI .624–1.981; <i>p</i> = .720).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Hypoalbuminemia is common in hospitalized HFmrEF patients. Low albumin levels, ACRs, and elevated UARs independently predicted long-term all-cause mortality, but not HF-related rehospitalization. The UAR and ACR did not provide a clinically significant predictive advantage over albumin levels alone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov Identifier: NCT05603390 (date of registration: 10.10.2020)</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiting Luo, Fan Yang, Yanlin He, Jin Lin, Weiqian Chen
Background
Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.
Methods
A narrative synthesis of literature published in the last 10 years was conducted utilizing keywords such as “Giant cell arteritis,” “Polymyalgia rheumatica,” “cellular senescence,” “senescence-associated secretory phenotype,” or “aging”.
Results
Evidence links cellular senescence and SASP to the pathogenesis of GCA and PMR, with key components like IL-6, IL-1β, and matrix metalloproteinases (MMPs) driving inflammation and tissue damage. We highlight how key SASP components, such as IL-6, IL-1β, and MMPs promote inflammation and tissue damage in GCA and PMR. Targeting SASP factors (senomorphics) or selectively eliminating senescent cells (senolytics) offers therapeutic potential. Further research into the mechanisms linking senescence to disease phenotypes is needed to develop effective therapies that mitigate disease progression and improve clinical outcomes.
Conclusion
We demonstrated age-related stress and senescence in the pathogenesis of GCA and PMR. We provide an overview of senomorphics, which have shown promise in clinical trials, and emphasize the need for further research to develop effective therapies.
{"title":"Cellular senescence in giant cell arteritis and polymyalgia rheumatica: From mechanisms to therapeutic opportunities","authors":"Yiting Luo, Fan Yang, Yanlin He, Jin Lin, Weiqian Chen","doi":"10.1111/eci.70166","DOIUrl":"10.1111/eci.70166","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative synthesis of literature published in the last 10 years was conducted utilizing keywords such as “Giant cell arteritis,” “Polymyalgia rheumatica,” “cellular senescence,” “senescence-associated secretory phenotype,” or “aging”.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Evidence links cellular senescence and SASP to the pathogenesis of GCA and PMR, with key components like IL-6, IL-1β, and matrix metalloproteinases (MMPs) driving inflammation and tissue damage. We highlight how key SASP components, such as IL-6, IL-1β, and MMPs promote inflammation and tissue damage in GCA and PMR. Targeting SASP factors (senomorphics) or selectively eliminating senescent cells (senolytics) offers therapeutic potential. Further research into the mechanisms linking senescence to disease phenotypes is needed to develop effective therapies that mitigate disease progression and improve clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We demonstrated age-related stress and senescence in the pathogenesis of GCA and PMR. We provide an overview of senomorphics, which have shown promise in clinical trials, and emphasize the need for further research to develop effective therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Moattar Raza Rizvi, Ankita Sharma, Faizan Z. Kashoo, Abdul Rahim Shaik, Mohamed K. Seyam, Basant Hamdy Elrefaey, Zeinab A. Ali, Ahmed Abdullah Asiri, Irshad Ahmad, Fuzail Ahmad
<div> <section> <h3> Background</h3> <p>Elderly frailty is a multifaceted clinical condition with diminished physiological reserves and increased stress susceptibility. It increases disability, hospitalization and mortality rates, requiring multidomain therapy. Structured physical-activity-based medical treatment can reduce frailty in physical, mental and emotional areas. This assessment distinguishes outcomes among validated frailty models (phenotype-based vs. deficit-accumulation) to highlight model-specific effects.</p> </section> <section> <h3> Objectives</h3> <p>The present systematic review assesses the efficacy of structured physical-activity-based physiotherapy in reducing frailty and enhancing physical, cognitive and emotional outcomes in persons aged ≥60. It highlights a critical data gap neglected by past studies by distinguishing intervention effects across proven frailty models (phenotype-based and deficit-accumulation frameworks).</p> </section> <section> <h3> Methodology</h3> <p>The review used PRISMA criteria and the PICOS framework to find relevant papers published between January 2002 and December 2025. PubMed, Scopus, Cochrane Library and Embase were searched. RCTs and longitudinal cohort studies on physiotherapy or structured physical-activity therapies (e.g. resistance training, aerobic conditioning, balance exercises, multimodal programs) for individuals aged ≥60 years were eligible. Frailty, physical performance and quality of life were evaluated. Cochrane Risk of Bias 2.0 was used for randomised studies and ROBINS-I for non-randomised designs.</p> </section> <section> <h3> Results</h3> <p>36 trials covered varied physiotherapy and structured physical-activity regimens. Participants, mostly aged ≥60, were mostly women (approximately two-thirds of the sample). The majority of investigations found that resistance training increased muscle strength and decreased frailty by 20%–35%. Exercises involving balance reduced fall risk by 25%–35%, while aerobic workouts improved gait and cardiovascular fitness. Multimodal interventions reversed frailty in 41%–50% of individuals and improved cognitive and emotional outcomes the highest. Physical performance, quality of life and functional independence improved across frailty models in weighted summaries.</p> </section> <section> <h3> Conclusion</h3> <p>Structured physical-activity-based physiotherapy therapies, especially multimodal programs, reduce frailty and enhance physical, cognitive and emotional resilience in older persons, highlighting their value in comprehensive geriatric care.</p>
背景：老年虚弱是一种多方面的临床状况，伴有生理储备减少和应激易感性增加。它增加了残疾率、住院率和死亡率，需要多领域治疗。有组织的以身体活动为基础的医疗可以减少身体、精神和情感方面的脆弱。该评估区分了经过验证的脆弱性模型（基于表型与缺陷积累）的结果，以突出模型特异性效应。目的：本系统综述评估结构化体力活动为基础的物理治疗在减少虚弱和提高身体，认知和情绪结果≥60岁的人的疗效。通过区分已证实的脆弱性模型（基于表型和缺陷积累框架）的干预效果，它突出了过去研究所忽视的一个关键数据缺口。方法：采用PRISMA标准和PICOS框架查找2002年1月至2025年12月期间发表的相关论文。检索PubMed、Scopus、Cochrane Library和Embase。适用于年龄≥60岁的个体的物理治疗或结构化体力活动治疗（如阻力训练、有氧调节、平衡运动、多模式项目）的随机对照试验和纵向队列研究。对虚弱程度、身体表现和生活质量进行评估。随机研究采用Cochrane Risk of Bias 2.0，非随机设计采用ROBINS-I。结果：36项试验涵盖了各种物理治疗和有组织的体育活动方案。参与者大多数年龄≥60岁，大多数是女性（约占样本的三分之二）。大多数调查发现，阻力训练可以增加20%-35%的肌肉力量，减少虚弱。平衡运动可以降低25%-35%的跌倒风险，而有氧运动可以改善步态和心血管健康。多模式干预在41%-50%的个体中逆转了虚弱，对认知和情绪结果的改善最大。在加权总结中，虚弱模型的身体表现、生活质量和功能独立性得到改善。结论：结构化的以身体活动为基础的物理治疗疗法，特别是多模式方案，可以减少老年人的脆弱性，提高他们的身体、认知和情绪恢复能力，突出了他们在综合老年护理中的价值。
{"title":"Reversing frailty: The transformative effects of structured physical-activity-based physiotherapy on physical, cognitive and emotional health in older adults—An evidence-based systematic review","authors":"Moattar Raza Rizvi, Ankita Sharma, Faizan Z. Kashoo, Abdul Rahim Shaik, Mohamed K. Seyam, Basant Hamdy Elrefaey, Zeinab A. Ali, Ahmed Abdullah Asiri, Irshad Ahmad, Fuzail Ahmad","doi":"10.1111/eci.70158","DOIUrl":"10.1111/eci.70158","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elderly frailty is a multifaceted clinical condition with diminished physiological reserves and increased stress susceptibility. It increases disability, hospitalization and mortality rates, requiring multidomain therapy. Structured physical-activity-based medical treatment can reduce frailty in physical, mental and emotional areas. This assessment distinguishes outcomes among validated frailty models (phenotype-based vs. deficit-accumulation) to highlight model-specific effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The present systematic review assesses the efficacy of structured physical-activity-based physiotherapy in reducing frailty and enhancing physical, cognitive and emotional outcomes in persons aged ≥60. It highlights a critical data gap neglected by past studies by distinguishing intervention effects across proven frailty models (phenotype-based and deficit-accumulation frameworks).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>The review used PRISMA criteria and the PICOS framework to find relevant papers published between January 2002 and December 2025. PubMed, Scopus, Cochrane Library and Embase were searched. RCTs and longitudinal cohort studies on physiotherapy or structured physical-activity therapies (e.g. resistance training, aerobic conditioning, balance exercises, multimodal programs) for individuals aged ≥60 years were eligible. Frailty, physical performance and quality of life were evaluated. Cochrane Risk of Bias 2.0 was used for randomised studies and ROBINS-I for non-randomised designs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>36 trials covered varied physiotherapy and structured physical-activity regimens. Participants, mostly aged ≥60, were mostly women (approximately two-thirds of the sample). The majority of investigations found that resistance training increased muscle strength and decreased frailty by 20%–35%. Exercises involving balance reduced fall risk by 25%–35%, while aerobic workouts improved gait and cardiovascular fitness. Multimodal interventions reversed frailty in 41%–50% of individuals and improved cognitive and emotional outcomes the highest. Physical performance, quality of life and functional independence improved across frailty models in weighted summaries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Structured physical-activity-based physiotherapy therapies, especially multimodal programs, reduce frailty and enhance physical, cognitive and emotional resilience in older persons, highlighting their value in comprehensive geriatric care.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Teresa Padro, Natàlia Muñoz-García, Marta Fanlo-Maresma, Virginia Esteve-Luque, Paula Cabré-Fernandez, Gemma Vilahur, Antoni Riera-Mestre, Lina Badimon, Xavier Pintó
Background
Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality.
Methods
We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment.
Results
Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median [IQR] CEC than non-ASCVD (p = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (p = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; p = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (p = 0.008; r = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile.
Conclusions
These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.
{"title":"HDL function and composition in atherothrombotic cardiovascular disease with very high HDL-C","authors":"Teresa Padro, Natàlia Muñoz-García, Marta Fanlo-Maresma, Virginia Esteve-Luque, Paula Cabré-Fernandez, Gemma Vilahur, Antoni Riera-Mestre, Lina Badimon, Xavier Pintó","doi":"10.1111/eci.70159","DOIUrl":"10.1111/eci.70159","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median [IQR] CEC than non-ASCVD (<i>p</i> = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (<i>p</i> = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; <i>p</i> = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (<i>p</i> = 0.008; <i>r</i> = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed Leishmania major CHIM for cutaneous leishmaniasis (CL).
Methods
A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.
Results
CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The Leishmania major CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host–parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.
Conclusions
CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.
{"title":"Harnessing controlled human infection models to accelerate vaccine development for neglected tropical diseases: Lessons from leishmaniasis","authors":"Vivak Parkash","doi":"10.1111/eci.70160","DOIUrl":"10.1111/eci.70160","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed <i>Leishmania major</i> CHIM for cutaneous leishmaniasis (CL).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The <i>Leishmania major</i> CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host–parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elif Harput, Cecilia Boccalini, Gregory Mathoux, John O. Prior, Nathalie Testart, Mario Jreige, Valentina Garibotto
Background
Alzheimer's disease (AD) is neuropathologically defined by the buildup of misfolded proteins such as extracellular amyloid-β (Aβ) and intracellular tau neurofibrillary tangles. AD also extends beyond these pathological processes, and additional mechanisms such as synaptic dysfunction, microglial activity, astrocytic neuroinflammation play an important role as biomarkers of AD progression. In vivo evaluation and quantification of these molecular processes are possible with positron emission tomography (PET) imaging. As disease-modifying therapies are entering clinical use, biomarkers' importance for early diagnosis and longitudinal monitoring of the disease increases.
Results
Aβ is the earliest signature of AD which can be measured with PET imaging, followed by tau-PET positivity, which is highly specific and central for staging and longitudinal monitoring. FDG-PET continues to serve as a gold standard for detecting neurodegeneration, challenged by emerging dual-phase PET protocols for amyloid and tau imaging, which integrate perfusion as a measure of neurodegeneration and pathology information in a single session, enhancing diagnostic efficiency. Synaptic density imaging reveals early synaptic loss linked to cognitive performance and decline. Neuroinflammation tracers can visualize microglial and astrocytic activation, contributing to disease onset and progression. Novel PET tracers targeting alpha-synuclein and TDP-43 show great promise for detecting co-pathologies which can contribute to AD clinical heterogeneity.
Conclusion
PET imaging has advanced the field by enabling visualization of AD-related changes and providing measurable outcomes for clinical trials and disease-modifying therapies. Imaging of related pathologies can further improve diagnostic accuracy and provide important insights into disease heterogeneity. Moving forward, integrating multiple PET biomarkers into personalized diagnostic approaches will be crucial.
{"title":"Mapping Alzheimer's disease heterogeneity with molecular imaging biomarkers","authors":"Elif Harput, Cecilia Boccalini, Gregory Mathoux, John O. Prior, Nathalie Testart, Mario Jreige, Valentina Garibotto","doi":"10.1111/eci.70163","DOIUrl":"10.1111/eci.70163","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is neuropathologically defined by the buildup of misfolded proteins such as extracellular amyloid-β (Aβ) and intracellular tau neurofibrillary tangles. AD also extends beyond these pathological processes, and additional mechanisms such as synaptic dysfunction, microglial activity, astrocytic neuroinflammation play an important role as biomarkers of AD progression. In vivo evaluation and quantification of these molecular processes are possible with positron emission tomography (PET) imaging. As disease-modifying therapies are entering clinical use, biomarkers' importance for early diagnosis and longitudinal monitoring of the disease increases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Aβ is the earliest signature of AD which can be measured with PET imaging, followed by tau-PET positivity, which is highly specific and central for staging and longitudinal monitoring. FDG-PET continues to serve as a gold standard for detecting neurodegeneration, challenged by emerging dual-phase PET protocols for amyloid and tau imaging, which integrate perfusion as a measure of neurodegeneration and pathology information in a single session, enhancing diagnostic efficiency. Synaptic density imaging reveals early synaptic loss linked to cognitive performance and decline. Neuroinflammation tracers can visualize microglial and astrocytic activation, contributing to disease onset and progression. Novel PET tracers targeting alpha-synuclein and TDP-43 show great promise for detecting co-pathologies which can contribute to AD clinical heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>PET imaging has advanced the field by enabling visualization of AD-related changes and providing measurable outcomes for clinical trials and disease-modifying therapies. Imaging of related pathologies can further improve diagnostic accuracy and provide important insights into disease heterogeneity. Moving forward, integrating multiple PET biomarkers into personalized diagnostic approaches will be crucial.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The emergence of real-world evidence (RWE) has significantly broadened the scope of clinical research in internal medicine, providing insights that extend beyond the constraints of randomized controlled trials (RCTs). RWE is generated from real-world data (RWD)—information collected outside experimental settings, such as routine clinical practice. Observational studies, including cohort, case–control and cross-sectional designs, are fundamental to RWE generation, enabling the examination of patient outcomes, treatment patterns and disease epidemiology as they naturally occur. The expanded use of registries and electronic health records (EHRs) has revolutionized data collection, offering both depth and breadth for large-scale, longitudinal studies. However, drawing causal inferences from observational research presents substantial methodological challenges, as confounding and bias arising from non-randomized treatment allocation and unmeasured variables can distort results. Data quality issues—such as missing data, exposure and outcome misclassification, and inconsistent variable definitions—further complicate analysis. Advanced statistical techniques, including propensity score matching and instrumental variable analysis, have been developed to mitigate the limitations due to confounding, yet cannot fully substitute for randomization. Transparent reporting, pre-registration of protocols, and adherence to standardized guidelines (e.g. STROBE) are essential to enhance rigor and reproducibility. Despite their challenges, observational studies remain indispensable for addressing clinical questions that cannot be answered by RCTs, informing practice and guiding healthcare policy. Careful study design, rigorous analysis and transparent reporting are crucial for maximizing the reliability and impact of real-world evidence in internal medicine.
{"title":"Real-world evidence and observational studies: Methodological challenges in clinical research","authors":"Carmine Zoccali, Giovanni Tripepi","doi":"10.1111/eci.70153","DOIUrl":"10.1111/eci.70153","url":null,"abstract":"<p>The emergence of real-world evidence (RWE) has significantly broadened the scope of clinical research in internal medicine, providing insights that extend beyond the constraints of randomized controlled trials (RCTs). RWE is generated from real-world data (RWD)—information collected outside experimental settings, such as routine clinical practice. Observational studies, including cohort, case–control and cross-sectional designs, are fundamental to RWE generation, enabling the examination of patient outcomes, treatment patterns and disease epidemiology as they naturally occur. The expanded use of registries and electronic health records (EHRs) has revolutionized data collection, offering both depth and breadth for large-scale, longitudinal studies. However, drawing causal inferences from observational research presents substantial methodological challenges, as confounding and bias arising from non-randomized treatment allocation and unmeasured variables can distort results. Data quality issues—such as missing data, exposure and outcome misclassification, and inconsistent variable definitions—further complicate analysis. Advanced statistical techniques, including propensity score matching and instrumental variable analysis, have been developed to mitigate the limitations due to confounding, yet cannot fully substitute for randomization. Transparent reporting, pre-registration of protocols, and adherence to standardized guidelines (e.g. STROBE) are essential to enhance rigor and reproducibility. Despite their challenges, observational studies remain indispensable for addressing clinical questions that cannot be answered by RCTs, informing practice and guiding healthcare policy. Careful study design, rigorous analysis and transparent reporting are crucial for maximizing the reliability and impact of real-world evidence in internal medicine.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Bertolotto, Daniela de Totero, Paolo Giannoni, Emanuela Barisione, Marco Grosso, Ennio Nano, Roberto Fiocca, Simona Pigozzi, Elisabetta Tedone, Luca Valle, Margherita Moriero, Daniela Verzola, Fabrizio Montecucco, Federico Carbone
Background
Interstitial lung diseases (ILDs) are characterized by progressive fibrosis, in which extracellular matrix remodelling is regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The MMP-9/TIMP-1 balance has been implicated in fibrogenesis, but its role in human ILD remains incompletely defined. This study aimed to assess the MMP-9/TIMP-1 ratio in BAL fluids of ILD patients, its relationship with fibrotic severity, and the cellular contribution of fibroblasts/myofibroblasts.
Methods
BAL samples from 48 consecutive ILD patients (non-fibrotic ILD, fibrotic ILD, idiopathic pulmonary fibrosis [IPF]) were analysed. MMP-9 and TIMP-1 concentrations were quantified by enzyme-linked immunosorbent assay (ELISA), and MMP-9 activity assessed by gelatin zymography. Fibroblasts/myofibroblasts were isolated from BAL of ILD patients and tested for TIMP-1 and MMP-9 release by ELISA, or protein expression by immunofluorescence. Published single-cell RNA sequencing datasets were reanalyzed (DESeq2 model) to define the cellular source of MMP-9 and TIMP-1.
Results
The MMP-9/TIMP-1 ratio was significantly reduced in BAL of patients with more advanced fibrosis, correlating with a higher presence of fibroblastic foci (p = .002) and collagen deposition (p < .001). This reduction was driven by both decreased MMP-9 and increased TIMP-1 levels. Zymography confirmed declining MMP-9 enzymatic activity across ILD subgroups. Fibroblasts, derived from BAL of ILD patients, displayed high TIMP-1 secretion but minimal MMP-9 release, consistent with their expression in immunofluorescence. Reanalysis of two independent scRNA-seq datasets confirmed predominant TIMP-1 expression in fibroblast/myofibroblast clusters, with low but detectable MMP-9 expression.
Conclusions
Fibroblast-driven MMP-9/TIMP-1 imbalance in BAL reflects fibrotic severity in ILD. The MMP-9/TIMP-1 ratio may represent a supportive biomarker for differential diagnosis and phenotyping of ILD, warranting validation in larger multicenter studies.
{"title":"Fibroblast-driven MMP-9/TIMP-1 imbalance in bronchoalveolar lavage reflects fibrotic progression in interstitial lung disease","authors":"Maria Bertolotto, Daniela de Totero, Paolo Giannoni, Emanuela Barisione, Marco Grosso, Ennio Nano, Roberto Fiocca, Simona Pigozzi, Elisabetta Tedone, Luca Valle, Margherita Moriero, Daniela Verzola, Fabrizio Montecucco, Federico Carbone","doi":"10.1111/eci.70162","DOIUrl":"10.1111/eci.70162","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Interstitial lung diseases (ILDs) are characterized by progressive fibrosis, in which extracellular matrix remodelling is regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The MMP-9/TIMP-1 balance has been implicated in fibrogenesis, but its role in human ILD remains incompletely defined. This study aimed to assess the MMP-9/TIMP-1 ratio in BAL fluids of ILD patients, its relationship with fibrotic severity, and the cellular contribution of fibroblasts/myofibroblasts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>BAL samples from 48 consecutive ILD patients (non-fibrotic ILD, fibrotic ILD, idiopathic pulmonary fibrosis [IPF]) were analysed. MMP-9 and TIMP-1 concentrations were quantified by enzyme-linked immunosorbent assay (ELISA), and MMP-9 activity assessed by gelatin zymography. Fibroblasts/myofibroblasts were isolated from BAL of ILD patients and tested for TIMP-1 and MMP-9 release by ELISA, or protein expression by immunofluorescence. Published single-cell RNA sequencing datasets were reanalyzed (DESeq2 model) to define the cellular source of MMP-9 and TIMP-1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The MMP-9/TIMP-1 ratio was significantly reduced in BAL of patients with more advanced fibrosis, correlating with a higher presence of fibroblastic foci (<i>p</i> = .002) and collagen deposition (<i>p</i> < .001). This reduction was driven by both decreased MMP-9 and increased TIMP-1 levels. Zymography confirmed declining MMP-9 enzymatic activity across ILD subgroups. Fibroblasts, derived from BAL of ILD patients, displayed high TIMP-1 secretion but minimal MMP-9 release, consistent with their expression in immunofluorescence. Reanalysis of two independent scRNA-seq datasets confirmed predominant TIMP-1 expression in fibroblast/myofibroblast clusters, with low but detectable MMP-9 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Fibroblast-driven MMP-9/TIMP-1 imbalance in BAL reflects fibrotic severity in ILD. The MMP-9/TIMP-1 ratio may represent a supportive biomarker for differential diagnosis and phenotyping of ILD, warranting validation in larger multicenter studies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/eci.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lidia Cornejo Fernández, Laura Gallardo-Nuell, Anna Pigem Rodeja, Irma Ramos-Oliver, Olga Delisau-Puig, Eloi Maldonado-Marcos, José Ignacio Rodríguez-Hermosa, Ramon Farrés Coll, Antoni Codina-Cazador, Jordi Mayneris-Perxachs, José Manuel Fernández-Real, Pere Planellas Giné
Backgorund
Adipose tissue has emerged as a prognostic factor in rectal cancer (RC), yet its metabolic role in tumour progression remains poorly understood. This study aims to characterise the metabolic profiles of subcutaneous (SAT) and visceral adipose tissue (VAT) in early and advanced tumours to investigate metabolic alterations that may influence tumour progression. Understanding these alterations could provide insights into mechanisms of rectal cancer and identify therapeutic targets.
Methods
Global metabolic profiles of 68 SAT and VAT samples from patients with RC were analyzed using high-performance chemical isotope labeling liquid chromatography mass spectrometry. Statistical analyses were stratified by clinical tumour invasion and disease stage.
Results
VAT exhibited distinct metabolic signatures between early and advanced tumour invasion. Advanced tumours (cT3-4) had a higher concentration of N-glycolylneuraminic acid and phenylacetylglutamine, whereas early invasive tumours (cT2) exhibited higher levels of dipeptides. Pathway enrichment analyses revealed dysregulations in taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, propanoate metabolism and cellular signalling pathways in advanced invasion. Propanoate metabolism emerged as a key pathway distinguishing early and advanced invasion stages. In SAT, metabolic changes aligned with overall disease stage. Early-stage disease was associated with a higher concentration of dipeptides, whereas advanced stages showed increased N-acetyl-agmatine and N-acetyl-L-noradrenaline.
Conclusions
Our study highlights significant metabolic alterations in adipose tissue associated with rectal cancer progression. VAT metabolism reflects tumour invasiveness, while SAT is more indicative of disease stage. Propanoate metabolism may serve as a biomarker for advanced invasion, offering potential for improved staging, reclassification and personalised therapeutic strategies.
{"title":"Adipose tissue metabolomics identifies disease stage and tumour invasiveness of rectal cancer","authors":"Lidia Cornejo Fernández, Laura Gallardo-Nuell, Anna Pigem Rodeja, Irma Ramos-Oliver, Olga Delisau-Puig, Eloi Maldonado-Marcos, José Ignacio Rodríguez-Hermosa, Ramon Farrés Coll, Antoni Codina-Cazador, Jordi Mayneris-Perxachs, José Manuel Fernández-Real, Pere Planellas Giné","doi":"10.1111/eci.70157","DOIUrl":"10.1111/eci.70157","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Backgorund</h3>\u0000 \u0000 <p>Adipose tissue has emerged as a prognostic factor in rectal cancer (RC), yet its metabolic role in tumour progression remains poorly understood. This study aims to characterise the metabolic profiles of subcutaneous (SAT) and visceral adipose tissue (VAT) in early and advanced tumours to investigate metabolic alterations that may influence tumour progression. Understanding these alterations could provide insights into mechanisms of rectal cancer and identify therapeutic targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Global metabolic profiles of 68 SAT and VAT samples from patients with RC were analyzed using high-performance chemical isotope labeling liquid chromatography mass spectrometry. Statistical analyses were stratified by clinical tumour invasion and disease stage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>VAT exhibited distinct metabolic signatures between early and advanced tumour invasion. Advanced tumours (cT3-4) had a higher concentration of N-glycolylneuraminic acid and phenylacetylglutamine, whereas early invasive tumours (cT2) exhibited higher levels of dipeptides. Pathway enrichment analyses revealed dysregulations in taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, propanoate metabolism and cellular signalling pathways in advanced invasion. Propanoate metabolism emerged as a key pathway distinguishing early and advanced invasion stages. In SAT, metabolic changes aligned with overall disease stage. Early-stage disease was associated with a higher concentration of dipeptides, whereas advanced stages showed increased N-acetyl-agmatine and N-acetyl-L-noradrenaline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study highlights significant metabolic alterations in adipose tissue associated with rectal cancer progression. VAT metabolism reflects tumour invasiveness, while SAT is more indicative of disease stage. Propanoate metabolism may serve as a biomarker for advanced invasion, offering potential for improved staging, reclassification and personalised therapeutic strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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