European Journal of Clinical Investigation最新文献_第6页

Insights into circulating CEACAM1 in insulin clearance and disease progression: Evidence from the Portuguese PREVADIAB2 study 循环中的 CEACAM1 在胰岛素清除和疾病进展中的作用：来自葡萄牙 PREVADIAB2 研究的证据。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-14 DOI: 10.1111/eci.14344

Rita S. Patarrão, Maria João Meneses, Hilda E. Ghadieh, Laura Herrera, Sérgio Duarte, Rogério T. Ribeiro, João F. Raposo, Verena Schmitt, Bernhard B. Singer, Amalia Gastaldelli, Carlos Penha-Gonçalves, Sonia M. Najjar, M. Paula Macedo

Background

Type 2 diabetes (T2DM) and obesity are characterized by altered insulin metabolism and action. Reduced hepatic insulin clearance is increasingly recognized as a key contributor to hyperinsulinemia and insulin resistance. CEACAM1 promotes hepatic insulin clearance, and its loss in hepatocytes is associated with reduced insulin clearance in mice and men. This study examines whether CEACAM1 circulating levels reflect compromised insulin metabolism and resistance in the PREVADIAB2 cohort.

Methods

A total of 1019 individuals from the PREVADIAB2 cohort were evaluated for diabetes by 75 g-OGTT and classified according to WHO 2019 criteria. CEACAM1 circulating levels were measured by ELISA, and insulin metabolism parameters were calculated. Hierarchical clustering of insulin metabolic indices and CEACAM1 levels was performed. Statistical significance was assessed using Kruskal–Wallis and Wilcoxon–Mann–Whitney tests.

Results

BMI, insulin resistance (HOMA-IR), and hepatic steatosis progressively increased with disease severity. Insulin secretion rose and its clearance declined in parallel to circulating CEACAM1 levels in prediabetes and T2DM, indicating compensatory hyperinsulinemia. Hierarchical metabolic clustering identified four clusters with distinct patterns and further showed that insulin clearance positively correlated with circulating CEACAM1, especially in individuals with normoglycemia, lower obesity and hepatic steatosis. This suggests that circulating CEACAM1 can reflect the status of hepatic insulin clearance.

Conclusions

This study demonstrates a progressive increase in insulin resistance and hyperinsulinemia in parallel to elevated BMI and hepatic steatosis prevalence, accompanied by declining circulating CEACAM1 levels. Cluster analysis further linked reduced insulin clearance to lower circulating CEACAM1 levels, suggesting its potential usefulness as a biomarker for metabolic disease progression.

背景：2型糖尿病（T2DM）和肥胖以胰岛素代谢和作用改变为特征。肝脏胰岛素清除率降低越来越被认为是高胰岛素血症和胰岛素抵抗的关键因素。CEACAM1促进肝脏胰岛素清除，其在肝细胞中的缺失与小鼠和男性胰岛素清除减少有关。本研究探讨了在PREVADIAB2队列中CEACAM1循环水平是否反映胰岛素代谢和抵抗受损。方法：通过75 g-OGTT对来自PREVADIAB2队列的1019例个体进行糖尿病评估，并根据WHO 2019标准进行分类。ELISA法检测血清CEACAM1水平，计算胰岛素代谢参数。对胰岛素代谢指标和CEACAM1水平进行分层聚类。采用Kruskal-Wallis检验和Wilcoxon-Mann-Whitney检验评估统计学显著性。结果：BMI、胰岛素抵抗（HOMA-IR）和肝脂肪变性随着疾病严重程度的增加而逐渐增加。糖尿病前期和T2DM患者胰岛素分泌升高，清除率下降，与循环CEACAM1水平平行，提示代偿性高胰岛素血症。分层代谢聚类鉴定出四个具有不同模式的聚类，并进一步表明胰岛素清除率与循环CEACAM1呈正相关，特别是在血糖正常、低肥胖和肝脂肪变性的个体中。这表明循环中的CEACAM1可以反映肝脏胰岛素清除的状态。结论：该研究表明，胰岛素抵抗和高胰岛素血症的进行性增加与BMI升高和肝脂肪变性患病率平行，并伴有循环CEACAM1水平下降。聚类分析进一步将胰岛素清除率降低与循环CEACAM1水平降低联系起来，提示其作为代谢性疾病进展的生物标志物的潜在用途。

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引用次数: 0

Mechanism and function of CEACAM1 splice isoforms CEACAM1剪接异构体的机制和功能。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-14 DOI: 10.1111/eci.14350

Kenneth J. Dery, Sonia M. Najjar, Nicole Beauchemin, John E. Shively, Jerzy W. Kupiec-Weglinski

Background

Alternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive.

Methods

This narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis-spliced variable exon 7 is discussed.

Results

The Ig variable-like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin-dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1-S. Homology studies of the muCEACAM1-S and huCEACAM1-S TM predict differences in their signal transduction pathways. Hypoxia-inducible factor 1-α (HIF-1-α) induces alternative splicing to produce CEACAM1-S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms.

Conclusion

More pre-clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies.

背景：替代剪接是基因转录后调控的基本机制。多功能跨膜糖蛋白受体癌胚抗原相关细胞粘附分子 1（CEACAM1）经历了广泛的剪接替代过程，从而在细胞信号、粘附以及免疫和代谢反应调节等方面实现了可调功能。外结构域和长短胞质尾不同的剪接异构体（CEACAM1-S/CEACAM1-L）具有不同的功能作用。CEACAM1 RNA剪接的调控机制仍未确定：本综述概述了目前有关 CEACAM1 剪接异构体的机制和功能的知识。从历史的角度探讨了糖基化 Ig 结构域、可变外显子 7 以及决定其信号转导途径的磷酸化事件的生物学意义。还讨论了使用反义小分子来靶向错误剪接的可变外显子 7 的问题：Ig可变样N结构域介导细胞粘附和免疫检查点抑制功能。跨膜（TM）结构域中的 Gly 和 Tyr 残基对二聚化至关重要。钙调蛋白、钙/钙调蛋白依赖性蛋白激酶 II delta（CamK2D）、肌动蛋白和附件蛋白 A2 是 CEACAM1-S 的结合伙伴。对 muCEACAM1-S 和 huCEACAM1-S TM 的同源性研究预测了它们信号转导途径的差异。缺氧诱导因子 1-α（HIF-1-α）诱导替代剪接，在有限的氧气条件下产生 CEACAM1-S。针对第7外显子的反义小分子可纠正短胞质尾和长胞质尾剪接异构体的错误表达：需要进行更多临床前和临床研究，以阐明 CEACAM1 RNA 剪接的精确机制，从而开发出新型治疗策略的靶向干预措施。

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引用次数: 0

Regulation of lipid storage and inflammation in the liver by CEACAM1 CEACAM1对肝脏脂质储存和炎症的调节。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-14 DOI: 10.1111/eci.14338

Sonia M. Najjar, John E. Shively

This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.

本综述侧重于肥胖症营养过剩时肝脏脂质储存和炎症的一个特殊方面。越来越多的证据表明，肝脏长期过量吸收脂肪酸（FA）与肝脏脂质储存和炎症密切相关，而且这两个过程通过一种平衡机制紧密相连。还有强有力的证据表明，细菌的脂质可能通过与脂质吸收相同的机制进入肠道，并且有一个固定的点来决定它们的吸收何时会触发肝脏的炎症反应。事实上，从肝脏大量吸收脂肪酸导致代谢功能障碍相关性脂肪性肝病（MASLD）发展为更严重的代谢功能障碍相关性脂肪性肝炎（MASH），取决于炎症的程度及其从急性发展为慢性的过程。因此，MASLD/MASH 与过量脂肪酸和渐进性炎症都是肝病的病因。我们首先介绍 CD36，它是十二指肠、肝脏和脂肪组织吸收脂肪酸和脂多糖（LPS）的主要角色。然后，我们将介绍 CEACAM1，它是调节肝脏新生脂肪生成和肝脏炎症反应的主要角色，以及它与肠细胞和肝细胞中 CD36 的双重关联。我们的结论是，CEACAM1 和 CD36 共同调控肝脏中脂滴的形成和炎症反应。

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引用次数: 0

The emerging role of Fusobacteria in carcinogenesis 镰刀菌在致癌过程中的新作用。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-14 DOI: 10.1111/eci.14353

Raisha J. Gibbs, Adam C. Chambers, Darryl J. Hill

The Fusobacterium genus comprises Gram-negative, obligate anaerobic bacteria that typically reside in the periodontium of the oral cavity, gastrointestinal tract, and female genital tract. The association of Fusobacterial spp. with colorectal tumours is widely accepted, with further evidence that this pathogen may also be implicated in the development of other malignancies. Fusobacterial spp. influence malignant cell behaviours and the tumour microenvironment in various ways, which can be related to the multiple surface adhesins expressed. These adhesins include Fap2 (fibroblast-activated protein 2), CpbF (CEACAM binding protein of Fusobacteria), FadA (Fusobacterium adhesin A) and FomA (Fusobacterial outer membrane protein A). This review outlines the influence of Fusobacteria in promoting cancer initiation and progression, impacts of therapeutic outcomes and discusses potential therapeutic interventions where appropriate.

镰刀菌属由革兰氏阴性、厌氧细菌组成，通常栖息于口腔、胃肠道和女性生殖道的牙周。镰刀菌属与结肠直肠肿瘤的关系已被广泛接受，有进一步证据表明，这种病原体也可能与其他恶性肿瘤的发生有关。镰刀菌属以各种方式影响恶性细胞行为和肿瘤微环境，这可能与表达的多种表面粘附蛋白有关。这些粘附蛋白包括 Fap2（成纤维细胞活化蛋白 2）、CpbF（镰刀菌的 CEACAM 结合蛋白）、FadA（镰刀菌粘附蛋白 A）和 FomA（镰刀菌外膜蛋白 A）。本综述概述了镰刀菌在促进癌症发生和发展方面的影响、对治疗结果的影响，并在适当的情况下讨论了潜在的治疗干预措施。

引用次数: 0

Residual risk prediction in anticoagulated patients with atrial fibrillation using machine learning: A report from the GLORIA-AF registry phase II/III 使用机器学习预测抗凝房颤患者的剩余风险：来自GLORIA-AF登记II/III期的报告

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-11 DOI: 10.1111/eci.14371

Yang Liu, Yang Chen, Ivan Olier, Sandra Ortega-Martorell, Bi Huang, Hironori Ishiguchi, Ho Man Lam, Kui Hong, Menno V. Huisman, Gregory Y. H. Lip, the GLORIA-AF Investigators

Background

Although oral anticoagulation decreases the risk of thromboembolism in patients with atrial fibrillation (AF), a residual risk of thrombotic events still exists. This study aimed to construct machine learning (ML) models to predict the residual risk in these patients.

Methods

Patients with newly diagnosed non-valvular AF were collected from the Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry. To predict the residual risk of the composite outcome of thrombotic events (defined as ischemic stroke, systemic embolism, transient ischemic attack and myocardial infarction), we constructed four prediction models using the logistic regression (LR), random forest, light gradient boosting machine and extreme gradient boosting machine ML algorithms. Performance was mainly evaluated by area under the receiver-operating characteristic curve (AUC), g-means and F1 scores. Feature importance was evaluated by SHapley Additive exPlanations.

Results

15,829 AF patients (70.33 ± 9.94 years old, 55% male) taking oral anticoagulation were included in our study, and 641 (4.0%) had residual risk, sustaining thrombotic events. In the test set, LR had the best performance with higher AUC trend of 0.712. RF has highest g-means of 0.295 and F1 score of 0.249. This was superior when compared with the CHA₂DS₂-VA score (AUC 0.698) and 2MACE score (AUC 0.696). Age, history of TE or MI, OAC discontinuation, eGFR and sex were identified as the top five factors associated with residual risk.

Conclusion

ML algorithms can improve the prediction of residual risk of anticoagulated AF patients compared to clinical risk factor-based scores.

背景：虽然口服抗凝降低心房颤动（AF）患者血栓栓塞的风险，但血栓事件的残余风险仍然存在。本研究旨在构建机器学习（ML）模型来预测这些患者的剩余风险。方法：从全球房颤患者长期口服抗血栓治疗登记中心（GLORIA-AF）收集新诊断的非瓣膜性房颤患者。为了预测血栓事件（定义为缺血性卒中、全身栓塞、短暂性缺血性发作和心肌梗死）复合结局的剩余风险，我们使用逻辑回归（LR）、随机森林、光梯度增强机和极端梯度增强机ML算法构建了四个预测模型。主要通过受试者工作特征曲线下面积（AUC）、g-means和F1评分来评价。特征重要性通过SHapley加性解释进行评估。结果：15829例口服抗凝的房颤患者（70.33±9.94岁，男性55%）纳入我们的研究，其中641例（4.0%）存在持续血栓形成事件的残留风险。在测试集中，LR表现最好，AUC趋势较高，为0.712。RF的最高g均值为0.295，F1得分为0.249。与CHA2DS2-VA评分（AUC 0.698）和2MACE评分（AUC 0.696）相比，这是优越的。年龄、TE或MI病史、OAC停药、eGFR和性别被确定为与剩余风险相关的前五大因素。结论：与基于临床危险因素评分相比，ML算法可以提高对抗凝房颤患者剩余风险的预测。

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引用次数: 0

Subtyping strokes using blood-based protein biomarkers: A high-throughput proteomics and machine learning approach 使用基于血液的蛋白质生物标志物分型中风：一种高通量蛋白质组学和机器学习方法。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-10 DOI: 10.1111/eci.14372

Shubham Misra, Praveen Singh, Shantanu Sengupta, Manoj Kushwaha, Zuhaibur Rahman, Divya Bhalla, Pumanshi Talwar, Manabesh Nath, Rahul Chakraborty, Pradeep Kumar, Amit Kumar, Praveen Aggarwal, Achal K. Srivastava, Awadh K. Pandit, Dheeraj Mohania, Kameshwar Prasad, Nishant K. Mishra, Deepti Vibha

Background

Rapid diagnosis of stroke and its subtypes is critical in early stages. We aimed to discover and validate blood-based protein biomarkers to differentiate ischemic stroke (IS) from intracerebral haemorrhage (ICH) using high-throughput proteomics.

Methods

We collected serum samples within 24 h from acute stroke (IS & ICH) and mimics patients. In the discovery phase, SWATH-MS proteomics identified differentially expressed proteins, which were validated using targeted proteomics in the validation phase. We conducted interaction network and pathway analyses using Cytoscape 3.10.0. We determined cut-off points using the Youden Index. We developed three prediction models using multivariable logistic regression analyses. We assessed the model performance using statistical tests.

Results

We included 20 IS and 20 ICH in the discovery phase and 150 IS, 150 ICH, and six stroke mimics in the validation phase. We quantified 375 proteins using SWATH-MS. Between IS and ICH, we discovered 20 differentially expressed proteins. In the validation phase, the combined prediction model including three biomarkers: GFAP (aOR 0.04; 95%CI .02–.11), MMP-9 (aOR .09; .03–.28), APO-C1 (aOR 5.76; 2.66–12.47) and clinical variables independently differentiated IS from ICH (accuracy: 92%, negative predictive value: 94%). Adding biomarkers to clinical variables improved discrimination by 26% (p < .001). Additionally, nine biomarkers differentiated IS from ICH within 6 h, while three biomarkers differentiated IS from mimics.

Conclusions

Our study demonstrated that GFAP, MMP-9 and APO-C1 biomarkers independently differentiated IS from ICH within 24 h and significantly improved the discrimination ability of prediction models. Temporal profiling of these biomarkers in the acute phase of stroke is warranted.

背景：早期快速诊断脑卒中及其亚型至关重要。我们旨在利用高通量蛋白质组学发现并验证基于血液的蛋白质生物标志物，以区分缺血性卒中（IS）和脑出血（ICH）。方法：采集急性脑卒中（IS和ICH）及模拟患者24 h内的血清样本。在发现阶段，SWATH-MS蛋白质组学鉴定了差异表达蛋白，并在验证阶段使用靶向蛋白质组学对其进行了验证。我们使用Cytoscape 3.10.0进行相互作用网络和途径分析。我们使用约登指数确定分界点。我们利用多变量逻辑回归分析建立了三个预测模型。我们使用统计检验来评估模型的性能。结果：我们在发现阶段纳入了20例IS和20例ICH，在验证阶段纳入了150例IS、150例ICH和6例卒中模拟。我们用SWATH-MS对375个蛋白进行定量。在IS和ICH之间，我们发现了20个差异表达蛋白。在验证阶段，联合预测模型包括三个生物标志物：GFAP (aOR 0.04；95%CI为0.02 - 0.11),MMP-9 (aOR为0.09；0.03 - 0.28), APO-C1 (aOR 5.76；2.66-12.47)和临床变量独立区分IS和ICH（准确率：92%，阴性预测值：94%）。结论：我们的研究表明GFAP、MMP-9和APO-C1生物标志物在24 h内独立区分IS和ICH，显著提高了预测模型的区分能力。这些生物标志物在中风急性期的时间谱分析是有必要的。

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引用次数: 0

Risk of cardiovascular disease in elderly subjects with obesity and liver fibrosis and the potential benefit of statin treatment 老年肥胖和肝纤维化患者心血管疾病的风险及他汀类药物治疗的潜在益处

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-05 DOI: 10.1111/eci.14368

Willy B. Theel, Vivian D. de Jong, Manuel Castro Cabezas, Diederick E. Grobbee, Johan W. Jukema, Stella Trompet

Background

Liver fibrosis progression is influenced by older age and cardiometabolic risk factors such as obesity and is associated with an increased risk of cardiovascular events. While statins may protect against cardiovascular complications, their effects in elderly individuals with obesity and liver fibrosis are unclear.

Method

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) database was used to evaluate the effect of pravastatin on major adverse cardiovascular events in an elderly population (>70 years). Subjects were categorized by BMI: lean (<25 kg/m²), overweight (25–29.9 kg/m²) and obese (≥30 kg/m²). Liver fibrosis was assessed using the FIB-4 index: low risk (<2.0), intermediate risk (2.0–2.66) and high risk (≥2.67). Time-to-event data were analysed using the Cox proportional hazards model, adjusted for confounders and compared the placebo and pravastatin groups.

Results

A total of 5.804 subjects were included. In the placebo group, the highest risk group (high FIB-4 and obesity) had a significantly higher hazard ratio for (non-)fatal stroke (HR 2.74; 95% CI 1.19–6.29) compared to the low FIB-4, lean BMI group. This risk disappeared in the same pravastatin group. Pravastatin did not affect other cardiovascular endpoints. All-cause mortality was significantly higher in subjects with lean weight and high FIB-4 on placebo (HR 1.88; 95% CI 1.14–3.11), but not on pravastatin (HR .58; 95% CI .28–1.20).

Conclusion

Elderly individuals with obesity and liver fibrosis are at higher risk for (non-)fatal stroke, which is reduced with pravastatin. Pravastatin also potentially lowers all-cause mortality in subjects with lean weight and liver fibrosis.

背景：肝纤维化的进展受年龄和心脏代谢危险因素（如肥胖）的影响，并与心血管事件风险增加相关。虽然他汀类药物可以预防心血管并发症，但其对肥胖和肝纤维化老年人的影响尚不清楚。方法：应用PROSPER数据库评估普伐他汀对老年人群（70岁~ 60岁）主要心血管不良事件的影响。受试者按BMI分为：瘦(2)、超重（25-29.9 kg/m2）和肥胖（≥30 kg/m2）。采用FIB-4指数评估肝纤维化：低危（结果：共纳入5.804例受试者）。在安慰剂组中，最高风险组（高FIB-4和肥胖）的（非）致死性卒中的风险比显著更高(HR 2.74；95% CI 1.19-6.29)，与低FIB-4、瘦BMI组相比。在同一个普伐他汀组，这种风险消失了。普伐他汀对其他心血管终点无影响。瘦体重和高FIB-4受试者的全因死亡率显著高于安慰剂组(HR 1.88；95% CI 1.14-3.11)，但普伐他汀组没有(HR .58；95% ci 0.28 -1.20)。结论：肥胖和肝纤维化的老年人发生（非）致死性卒中的风险较高，普伐他汀可降低这一风险。普伐他汀还可能降低瘦体重和肝纤维化患者的全因死亡率。

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引用次数: 0

Impact of oncologic diseases on outcome in patients with severe isolated tricuspid regurgitation 肿瘤疾病对严重孤立性三尖瓣反流患者预后的影响。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-12-02 DOI: 10.1111/eci.14367

Varius Dannenberg, Flora Zschocke, Kseniya Halavina, Katharina Mascherbauer, Gregor Heitzinger, Matthias Koschutnik, Carolina Donà, Christian Nitsche, Andreas A. Kammerlander, Georg Spinka, Max-Paul Winter, Philipp E. Bartko, Christian Hengstenberg, Jutta Bergler-Klein, Georg Goliasch, Matthias Schneider-Reigbert

Background

Severe tricuspid regurgitation (TR) is associated with high morbidity and mortality. Isolated TR, defined as TR without overt heart disease, is typical and offers limited cardiac treatment options other than interventional repair or replacement. Survival history of cancer or active cancer treatment may lead to an unnecessary delay of TR treatment.

Methods

We included all patients diagnosed with severe TR at the Medical University of Vienna between 2003 and 2016 who had normal left ventricular function and no other valvular lesions. Outcome analysis was performed on cancer type, status and the number of organs affected by cancer.

Results

A total of 973 patients were included. 182 (19%) patients had cancer, 52 were active and 130 had a history of cancer at the time of TR diagnosis. Oncologic patients were divided into subgroups of gastrointestinal, skin, glands, gynaecological, breast, urogenital, lung and other cancers. Ten-year mortality of patients with cancer was higher than those without cancer (p < 0.001). Multivariate analysis adjusting for age did not reveal significantly higher mortality in patients with a history of cancer compared to patients without cancer (p = 0.59). Patients with lung, active, or multi-organ cancer showed the highest mortality.

Conclusions

Mortality in patients with severe isolated TR is high and increased by active or multi-organ cancer but not by a history of cancer. These patients should be discussed in interdisciplinary cardio-oncology teams to avoid delaying life-saving treatment of TR and cancer.

背景：严重三尖瓣反流（TR）与高发病率和死亡率相关。孤立性TR，定义为没有明显心脏疾病的TR，是典型的，除了介入修复或置换之外，提供有限的心脏治疗选择。癌症生存史或积极的癌症治疗可能导致TR治疗的不必要延误。方法：我们纳入了2003年至2016年间在维也纳医科大学诊断为严重TR的所有左心室功能正常且无其他瓣膜病变的患者。结果分析癌症的类型、状态和受癌症影响的器官数量。结果：共纳入973例患者。182例（19%）患者患有癌症，52例为活动性，130例在TR诊断时有癌症史。肿瘤患者被分为胃肠道、皮肤、腺体、妇科、乳腺癌、泌尿生殖系统、肺癌和其他癌症亚组。结论：严重孤立性TR患者的死亡率较高，且与活动性或多器官癌症相关，而与癌症病史无关。这些患者应在跨学科的心脏肿瘤学团队中进行讨论，以避免延迟TR和癌症的救生治疗。

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引用次数: 0

Association between insulin-associated gene polymorphisms and new-onset diabetes mellitus in statin-treated patients 胰岛素相关基因多态性与他汀类药物治疗患者新发糖尿病的关系

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-11-30 DOI: 10.1111/eci.14366

Minju Park, Jung Sun Kim, Yoon-A Park, Da Hoon Lee, Seo-A Choi, Yoonkyung Chang, Tae-Jin Song, Hye Sun Gwak, Jeong Yee

Background

While statins are effective at managing lipid levels, there is growing evidence for new-onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP-related genes and NODM.

Methods

We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP-related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.

Results

A total of 602 patients were analysed, including 71 (11.8%) with statin-induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin-induced NODM lost their significance in patients with DM prior to statin therapy.

Conclusion

This study revealed the ISP-related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin-induced NODM. Our findings suggest a potential mechanism of statin-induced NODM related to ISP-related genetic variants.

背景：虽然他汀类药物对控制血脂水平有效，但越来越多的证据表明他汀类药物可用于新发糖尿病（NODM）。他汀类药物抑制胰岛素信号通路（ISP）是其潜在机制之一；然而，大多数研究都局限于体外环境。因此，本研究旨在确定isp相关基因与NODM之间的遗传关联。方法：对2021年2月至2021年5月前瞻性采集的样本进行回顾性分析。在isp相关基因中，我们选择了11个候选基因（IGF1、IGF2、IGF1R、INSR、IRS1、IRS2、PIK3CA、PIK3CB、PIK3R1、AKT1和AKT2）。另一项分析对他汀类药物治疗前的糖尿病患者和对照组进行了比较，以确定单核苷酸多态性（snp）是否对他汀类药物特异性。结果：共分析602例患者，其中他汀类药物诱导NODM 71例（11.8%）。调整后发现IGF1R rs2715439、INSR rs1799817、INSR rs2059807和PIK3R1 rs3730089与NODM独立相关。在另一项分析中，所有与他汀类药物诱导的NODM相关的snp在他汀类药物治疗前的DM患者中失去了意义。结论：本研究揭示了与isp相关的遗传效应，特别是涉及到INSR、IGF1R和PIK3R1等基因在他汀类药物诱导的NODM的发展中。我们的研究结果表明，他汀类药物诱导NODM的潜在机制与isp相关的遗传变异有关。

{"title":"Association between insulin-associated gene polymorphisms and new-onset diabetes mellitus in statin-treated patients","authors":"Minju Park, Jung Sun Kim, Yoon-A Park, Da Hoon Lee, Seo-A Choi, Yoonkyung Chang, Tae-Jin Song, Hye Sun Gwak, Jeong Yee","doi":"10.1111/eci.14366","DOIUrl":"10.1111/eci.14366","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>While statins are effective at managing lipid levels, there is growing evidence for new-onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP-related genes and NODM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP-related genes, we selected 11 candidate genes (<i>IGF1</i>, <i>IGF2</i>, <i>IGF1R</i>, <i>INSR</i>, <i>IRS1</i>, <i>IRS2</i>, <i>PIK3CA</i>, <i>PIK3CB</i>, <i>PIK3R1</i>, <i>AKT1</i> and <i>AKT2</i>). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 602 patients were analysed, including 71 (11.8%) with statin-induced NODM. After adjustment, <i>IGF1R</i> rs2715439, <i>INSR</i> rs1799817, <i>INSR</i> rs2059807 and <i>PIK3R1</i> rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin-induced NODM lost their significance in patients with DM prior to statin therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study revealed the ISP-related genetic effects, specifically involving genes such as <i>INSR</i>, <i>IGF1R</i> and <i>PIK3R1</i>, in the development of statin-induced NODM. Our findings suggest a potential mechanism of statin-induced NODM related to ISP-related genetic variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754913","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}

引用次数: 0

Circulating Fetuin-A concentrations in rheumatic diseases: a systematic review and meta-analysis. 风湿性疾病中的循环 Fetuin-A 浓度：系统回顾和荟萃分析。

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation

Pub Date : 2024-11-28 DOI: 10.1111/eci.14365

Biagio Di Lorenzo, Stefano Zoroddu, Arduino A Mangoni, Panagiotis Paliogiannis, Gian Luca Erre, Ciriaco Carru, Angelo Zinellu

Background: Rheumatic diseases (RDs) include a broad group of disabling conditions with different phenotypes, from autoimmune to autoinflammatory, degenerative, metabolic or mixed manifestations. With the continuous efforts to identify therapeutic targets for new biologic drugs to treat overt clinical manifestations, research is also focusing on the discovery of new biomarkers to diagnose and manage early disease stages. In this context, we conducted a systematic review and meta-analysis of Fetuin-A (FtA), a glycoprotein synthesized by the liver that participates in several biological processes and has been proposed as a biomarker for several disorders, including rheumatoid arthritis.

Methods: A systematic search in PubMed, Scopus and Web of Science, from inception to the 24th of August 2024, led to the identification of 13 manuscripts from 219 records; six additional studies were identified through reference hand-search, for a total of 19 studies.

Results: There was a significant decrease in FtA concentrations in RD patients (standardized mean difference, SMD = -.91; 95% CI -1.43 to -.39, p = .001), with no substantial contribution from any individual study nor publication bias. The effect size was significantly associated with erythrocyte sedimentation rate, various lipid fractions, geographical area of study conduction, study design and specific type of RD.

Conclusion: In conclusion, our study identified significant reductions in FtA concentrations in RD patients versus healthy controls. These alterations were significantly associated with specific study and patient characteristics. Further research is required to identify the exact pathophysiological mechanisms underlying these alterations and the possible utility of measuring FtA for the diagnosis and management of RDs.

背景：风湿性疾病（RDs）包括一大类表型各异的致残性疾病，从自身免疫性疾病到自身炎症性疾病、退行性疾病、代谢性疾病或混合性疾病。随着人们不断努力寻找新生物药物的治疗靶点以治疗明显的临床表现，研究工作也侧重于发现新的生物标志物以诊断和管理疾病的早期阶段。在此背景下，我们对Fetuin-A（FtA）进行了系统综述和荟萃分析。FtA是一种由肝脏合成的糖蛋白，参与多种生物过程，已被提议作为包括类风湿性关节炎在内的多种疾病的生物标志物：在 PubMed、Scopus 和 Web of Science 上进行了系统检索，从 219 条记录中筛选出 13 篇手稿；通过手工检索参考文献又筛选出 6 项研究，共计 19 项研究：RD患者的FtA浓度明显下降（标准化平均差，SMD = -.91; 95% CI -1.43 to -.39，p = .001），没有任何一项研究对其有实质性影响，也没有发表偏倚。效应大小与红细胞沉降率、各种脂质组分、研究开展的地理区域、研究设计和具体的 RD 类型有明显关联：总之，我们的研究发现，与健康对照组相比，RD 患者的 FtA 浓度明显降低。这些变化与特定的研究和患者特征密切相关。要确定这些变化的确切病理生理机制，以及测量 FtA 对诊断和管理 RD 的可能作用，还需要进一步的研究。

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引用次数: 0