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Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.
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Neoplasias , Transducción de Señal , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Animales , Carcinogénesis/patología , Carcinogénesis/metabolismo , Carcinogénesis/genéticaRESUMEN
Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.
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Hypertension is a pervasive and widespread health condition that poses a significant risk factor for cardiovascular disease, which includes conditions such as heart attack, stroke, and heart failure. Despite its widespread occurrence, the exact cause of hypertension remains unknown, and the mechanisms underlying the progression from prehypertension to hypertension require further investigation. Recent proteomic studies have shown promising results in uncovering potential biomarkers related to disease development. In this study, serum proteomic data collected from Qatar Biobank were analyzed to identify altered protein expression between individuals with normal blood pressure, prehypertension, and hypertension and to elucidate the biological pathways contributing to this disease. The results revealed a cluster of proteins, including the SRC family, CAMK2B, CAMK2D, TEC, GSK3, VAV, and RAC, which were markedly upregulated in patients with hypertension compared to those with prehypertension (fold change ≥ 1.6 or ≤-1.6, area under the curve ≥ 0.8, and q-value < 0.05). Pathway analysis showed that the majority of these proteins play a role in actin cytoskeleton remodeling. Actin cytoskeleton reorganization affects various biological processes that contribute to the maintenance of blood pressure, including vascular tone, endothelial function, cellular signaling, inflammation, fibrosis, and mechanosensing. Therefore, the findings of this study suggest a potential novel role of actin cytoskeleton-related proteins in the progression from prehypertension to hypertension. The present study sheds light on the underlying pathological mechanisms involved in hypertension and could pave the way for new diagnostic and therapeutic approaches for the treatment of this disease.
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Citoesqueleto de Actina , Hipertensión , Proteómica , Femenino , Humanos , Masculino , Citoesqueleto de Actina/metabolismo , Biomarcadores , Presión Sanguínea , Hipertensión/metabolismo , Prehipertensión/metabolismo , Proteoma/metabolismo , Proteómica/métodos , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Proteínas Proto-Oncogénicas c-vav/genética , Proteínas Proto-Oncogénicas c-vav/metabolismo , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismoRESUMEN
Introduction: Pre-hypertension is a prevalent condition among the adult population worldwide. It is characterized by asymptomatic elevations in blood pressure beyond normal levels but not yet reaching the threshold for hypertension. If left uncontrolled, pre-hypertension can progress to hypertension, thereby increasing the risk of serious complications such as heart disease, stroke, kidney damage, and others. Objective: The precise mechanisms driving the progression of hypertension remain unknown. Thus, identifying the metabolic changes associated with this condition can provide valuable insights into potential markers or pathways implicated in the development of hypertension. Methods: In this study, we utilized untargeted metabolomics profiling, which examines over 1,000 metabolites to identify novel metabolites contributing to the progression from pre-hypertension to hypertension. Data were collected from 323 participants through Qatar Biobank. Results: By comparing metabolic profiles between pre-hypertensive, hypertensive and normotensive individuals, six metabolites including stearidonate, hexadecadienoate, N6-carbamoylthreonyladenosine, 9 and 13-S-hydroxyoctadecadienoic acid (HODE), 2,3-dihydroxy-5-methylthio- 4-pentenoate (DMTPA), and linolenate were found to be associated with increased risk of hypertension, in both discovery and validation cohorts. Moreover, these metabolites showed a significant diagnostic performance with area under curve >0.7. Conclusion: These findings suggest possible biomarkers that can predict the risk of progression from pre-hypertension to hypertension. This will aid in early detection, diagnosis, and management of this disease as well as its associated complications.
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INTRODUCTION: Alzheimer's Disease (AD) is complex and novel approaches are urgently needed to aid in diagnosis. Blood is frequently used as a source for biomarkers; however, its complexity prevents proper detection. The analytical power of metabolomics, coupled with statistical tools, can assist in reducing this complexity. OBJECTIVES: Thus, we sought to validate a previously proposed panel of metabolic blood-based biomarkers for AD and expand our understanding of the pathological mechanisms involved in AD that are reflected in the blood. METHODS: In the validation cohort serum and plasma were collected from 25 AD patients and 25 healthy controls. Serum was analysed for metabolites using nuclear magnetic resonance (NMR) spectroscopy, while plasma was tested for markers of neuronal damage and AD hallmark proteins using single molecule array (SIMOA). RESULTS: The diagnostic performance of the metabolite biomarker panel was confirmed using sparse-partial least squares discriminant analysis (sPLS-DA) with an area under the curve (AUC) of 0.73 (95% confidence interval: 0.59-0.87). Pyruvic acid and valine were consistently reduced in the discovery and validation cohorts. Pathway analysis of significantly altered metabolites in the validation set revealed that they are involved in branched-chain amino acids (BCAAs) and energy metabolism (glycolysis and gluconeogenesis). Additionally, strong positive correlations were observed for valine and isoleucine between cerebrospinal fluid p-tau and t-tau. CONCLUSIONS: Our proposed panel of metabolites was successfully validated using a combined approach of NMR and sPLS-DA. It was discovered that cognitive-impairment-related metabolites belong to BCAAs and are involved in energy metabolism.
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Enfermedad de Alzheimer , Aminoácidos , Humanos , Enfermedad de Alzheimer/diagnóstico , Metabolómica , Aminoácidos de Cadena Ramificada , Valina , BiomarcadoresRESUMEN
Apolipoproteins (APOs) are vital structural components of plasma lipoproteins that are involved in lipid metabolism and transport. Recent studies have reported an association between apolipoprotein dysregulation and the onset of a variety of human cancers; however, the role of certain APOs in cancer development remains unknown. Based on recent work, we hypothesize that APOs might be involved in the onset of cancer, with a focus on the most common cancers, including breast, lung, gynecological, colorectal, thyroid, gastric, pancreatic, hepatic, and prostate cancers. This review will focus on the evidence supporting this hypothesis, the mechanisms linking APOs to the onset of cancer, and the potential clinical relevance of its various inhibitors.
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The accurate diagnosis of small-cell lung cancer (SCLC) is crucial, as treatment strategies differ from those of other lung cancers. This systematic review aims to identify proteins differentially expressed in SCLC compared to normal lung tissue, evaluating their potential utility in diagnosing and prognosing the disease. Additionally, the study identifies proteins differentially expressed between SCLC and large cell neuroendocrine carcinoma (LCNEC), aiming to discover biomarkers distinguishing between these two subtypes of neuroendocrine lung cancers. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted across PubMed/MEDLINE, Scopus, Embase, and Web of Science databases. Studies reporting proteomics information and confirming SCLC and/or LCNEC through histopathological and/or cytopathological examination were included, while review articles, non-original articles, and studies based on animal samples or cell lines were excluded. The initial search yielded 1705 articles, and after deduplication and screening, 16 articles were deemed eligible. These studies revealed 117 unique proteins significantly differentially expressed in SCLC compared to normal lung tissue, along with 37 unique proteins differentially expressed between SCLC and LCNEC. In conclusion, this review highlights the potential of proteomics technology in identifying novel biomarkers for diagnosing SCLC, predicting its prognosis, and distinguishing it from LCNEC.
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The High-Mobility Group Box-1 (HMGB1), a non-histone chromatin-associated protein, plays a crucial role in cancer growth and response to therapy as it retains a pivotal role in promoting both cell death and survival. HMGB1 has been reported to regulate several signaling pathways engaged in inflammation, genome stability, immune function, cell proliferation, cell autophagy, metabolism, and apoptosis. However, the association between HMGB1 and cancer is complex and its mechanism in tumorigenesis needs to be further elucidated. This review aims to understand the role of HMGB1 in human malignancies and discuss the signaling pathways linked to this process to provide a comprehensive understanding on the association of HMGB1 with carcinogenesis. Further, we will review the role of HMGB1 as a target/biomarker for cancer therapy, the therapeutic strategies used to target this protein, and its potential role in preventing or treating cancers. In light of the recent growing evidence linking HMGB1 to cancer progression, we think that it may be suggested as a novel and emergent therapeutic target for cancer therapy. Hence, HMGB1 warrants paramount investigation to comprehensively map its role in tumorigenesis.
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Proteína HMGB1 , Neoplasias , Humanos , Autofagia/genética , Carcinogénesis , Transformación Celular Neoplásica , Proteína HMGB1/metabolismo , Inflamación , Transducción de SeñalRESUMEN
Gliomas, which arise from glial cells in the brain, remain a significant challenge due to their location and resistance to traditional treatments. Despite research efforts and advancements in healthcare, the incidence of gliomas has risen dramatically over the past two decades. The dysregulation of microRNAs (miRNAs) has prompted the creation of therapeutic agents that specially target them. However, it has been reported that they are involved in complex signaling pathways that contribute to the loss of expression of tumor suppressor genes and the upregulation of the expression of oncogenes. In addition, numerous miRNAs promote the development, progression, and recurrence of gliomas by targeting crucial proteins and enzymes involved in metabolic pathways such as glycolysis and oxidative phosphorylation. However, the complex interplay among these pathways along with other obstacles hinders the ability to apply miRNA targeting in clinical practice. This highlights the importance of identifying specific miRNAs to be targeted for therapy and having a complete understanding of the diverse pathways they are involved in. Therefore, the aim of this review is to provide an overview of the role of miRNAs in the progression and prognosis of gliomas, emphasizing the different pathways involved and identifying potential therapeutic targets.
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Multiple myeloma (MM) is an incurable hematological cancer. It is preceded by monoclonal gammopathy of uncertain significance (MGUS)-an asymptomatic phase. It has been demonstrated that early detection increases the 5-year survival rate. However, blood-based biomarkers that enable early disease detection are lacking. Metabolomic and lipoprotein subfraction variable profiling is gaining traction to expand our understanding of disease states and, more specifically, for identifying diagnostic markers in patients with hematological cancers. This study aims to enhance our understanding of multiple myeloma (MM) and identify candidate metabolites, allowing for a more effective preventative treatment. Serum was collected from 25 healthy controls, 20 patients with MGUS, and 30 patients with MM. 1H-NMR (Nuclear Magnetic Resonance) spectroscopy was utilized to evaluate serum samples. The metabolite concentrations were examined using multivariate, univariate, and pathway analysis. Metabolic profiles of the MGUS patients revealed lower levels of alanine, lysine, leucine but higher levels of formic acid when compared to controls. However, metabolic profiling of MM patients, compared to controls, exhibited decreased levels of total Apolipoprotein-A1, HDL-4 Apolipoprotein-A1, HDL-4 Apolipoprotein-A2, HDL Free Cholesterol, HDL-3 Cholesterol and HDL-4 Cholesterol. Lastly, metabolic comparison between MGUS to MM patients primarily indicated alterations in lipoproteins levels: Total Cholesterol, HDL Cholesterol, HDL Free Cholesterol, Total Apolipoprotein-A1, HDL Apolipoprotein-A1, HDL-4 Apolipoprotein-A1 and HDL-4 Phospholipids. This study provides novel insights into the serum metabolic and lipoprotein subfraction changes in patients as they progress from a healthy state to MGUS to MM, which may allow for earlier clinical detection and treatment.
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BACKGROUND: Small cell lung cancer (SCLC) is highly aggressive with limited therapeutic options and a poor prognosis. Moreover, noninvasive biomarker tools for detecting disease and monitoring treatment response are lacking. To address this, we evaluated serum biomarkers of extracellular matrix proteins not previously explored in SCLC. METHODS: We measured biomarkers in the serum of 16 patients with SCLC before and after chemotherapy as well as in the serum of 11 healthy individuals. RESULTS: Our findings demonstrated that SCLC serum had higher levels of collagen type I degradation, collagen type III formation, and collagen type XI formation than healthy controls. In addition, we observed higher levels of type XIX and XXII collagens, fibrinogen, and von Willebrand factor A formation in SCLC serum. The formation of type I collagen did not exhibit any discernible variation. However, we observed a decrease in the degradation of type I collagen following chemotherapy. CONCLUSION: Overall, our findings revealed elevated levels of collagen and blood-clotting markers in the serum of SCLC patients, indicating the potential of ECM proteins as noninvasive biomarkers for SCLC.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Colágeno Tipo I , Pronóstico , Biomarcadores , Colágeno , Proteínas de la Matriz Extracelular , Neoplasias Pulmonares/tratamiento farmacológico , Biomarcadores de TumorRESUMEN
Advancement in the development of molecular sequencing platforms has identified infectious bacteria or viruses that trigger the dysregulation of a set of genes inducing the epithelial-mesenchymal transition (EMT) event. EMT is essential for embryogenesis, wound repair, and organ development; meanwhile, during carcinogenesis, initiation of the EMT can promote cancer progression and metastasis. Recent studies have reported that interactions between the host and dysbiotic microbiota in different tissues and organs, such as the oral and nasal cavities, esophagus, stomach, gut, skin, and the reproductive tract, may provoke EMT. On the other hand, it is revealed that certain microorganisms display a protective role against cancer growth, indicative of possible therapeutic function. In this review, we summarize recent findings elucidating the underlying mechanisms of pathogenic microorganisms, especially the microbiota, in eliciting crucial regulator genes that induce EMT. Such an approach may help explain cancer progression and pave the way for developing novel preventive and therapeutic strategies.
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Hypertension is a major risk factor for cardiovascular disease (CVD) as well as a major contributor to all-cause mortality and disability worldwide. The pathophysiology of hypertension is highly attributed to a dysfunctional endothelium and vascular remodeling. Despite the wide use of pharmacological therapies that modulate these pathways, a large percentage of patients continue to have uncontrolled hypertension, and the use of non-pharmacological interventions is increasingly investigated. Among these, caloric restriction (CR) appears to be a promising nutritional intervention for the management of hypertension. However, the mechanisms behind this effect are not yet fully understood, although an evolving view supports a significant impact of CR on vascular structure and function, specifically at the level of vascular endothelial cells, vascular smooth muscle cells along with their extracellular matrix (ECM). Accumulating evidence suggests that CR promotes endothelium-dependent vasodilation through activating eNOS and increasing nitric oxide (NO) levels through multiple cascades involving modulation of oxidative stress, autophagy, and inflammation. Indeed, CR diminishes phenotypic shift, and suppresses proliferation and migration of VSMCs via pathways involving NO and mTOR. By regulating transforming growth factor-ß and matrix metalloproteinases, CR appears to reduce ECM and collagen deposition in vascular walls. Here, we offer a detailed discussion of how these mechanisms contribute to CR's influence on reducing blood pressure. Such mechanisms could then provide a valuable foundation on which to base new therapeutic interventions for hypertension.
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Restricción Calórica , Hipertensión , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Humanos , Hipertensión/metabolismo , Óxido Nítrico/metabolismo , VasodilataciónRESUMEN
BACKGROUND: The thrombin generation (TG) assay, which measures global coagulation, has mainly been used as a research tool to investigate thrombotic and bleeding disorders. Recently, Diagnostica Stago launched the ST Genesia, a fully automated system to perform "routine version" of this assay. The objectives of this study were to evaluate the imprecision compared with the previous method, Thrombinoscope CAT, and to establish reference intervals. METHODS: Thrombin generation was measured in platelet-poor citrated plasma from 20 normal controls (fresh and after freezing at -80°C up to 12-13 weeks) on CAT and ST Genesia in duplicate to estimate the total variation, and within and between variations. The reference intervals were estimated nonparametrically in 30 men, 30 women taking combined oral contraceptives (COCs), and 30 women not taking COCs. These were sampled in both Vacutainer and Monovette tubes (i.e., tubes with a high and minimal contact activation, respectively). RESULTS: Freezing had minimal effects. Imprecision was comparable between the ST Genesia and CAT, with a strong correlation between the two methods. TG was higher when sampled in Vacutainer than in Monovette. We observed a distinct difference between women taking and not taking COCs, whereas men and women not taking COC were quite similar. CONCLUSIONS: Thrombin generation on ST Genesia showed an analytical variation similar to that of CAT. The results depended on the type of sample tubes; thus, reference intervals must be established for the collection tubes used in each laboratory. Furthermore, a considerable difference was observed between women using and not using COCs.
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BACKGROUND: Early detection of small cell lung cancer (SCLC) crucially demands highly reliable markers. Growing evidence suggests that extracellular vesicles carry tumor cell-specific cargo suitable as protein markers in cancer. Quantitative proteomic profiling of circulating microvesicles and exosomes can be a high-throughput platform for discovery of novel molecular insights and putative markers. Hence, this study aimed to investigate proteome dynamics of plasma-derived microvesicles and exosomes in newly diagnosed SCLC patients to improve early detection. METHODS: Plasma-derived microvesicles and exosomes from 24 healthy controls and 24 SCLC patients were isolated from plasma by either high-speed- or ultracentrifugation. Proteins derived from these extracellular vesicles were quantified using label-free mass spectrometry and statistical analysis was carried out aiming at identifying significantly altered protein expressions between SCLC patients and healthy controls. Furthermore, significantly expressed proteins were subjected to functional enrichment analysis to identify biological pathways implicated in SCLC pathogenesis. RESULTS: Based on fold change (FC) ≥ 2 or ≤ 0.5 and AUC ≥ 0.70 (p < 0.05), we identified 10 common and 16 and 17 unique proteins for microvesicles and exosomes, respectively. Among these proteins, we found dysregulation of coagulation factor XIII A (Log2 FC = - 1.1, p = 0.0003, AUC = 0.82, 95% CI: 0.69-0.96) and complement factor H-related protein 4 (Log2 FC = 1.2, p = 0.0005, AUC = 0.82, 95% CI; 0.67-0.97) in SCLC patients compared to healthy individuals. Our data may indicate a novel tumor-suppressing role of blood coagulation and involvement of complement activation in SCLC pathogenesis. CONCLUSIONS: In comparing SCLC patients and healthy individuals, several differentially expressed proteins were identified. This is the first study showing that circulating extracellular vesicles may encompass specific proteins with potential diagnostic attributes for SCLC, thereby opening new opportunities as novel non-invasive markers.
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BACKGROUND: Alzheimer's Disease (AD) is a complex and multifactorial disease and novel approaches are needed to illuminate the underlying pathology. Metabolites comprise the end-product of genes, transcripts, and protein regulations and might reflect disease pathogenesis. Blood is a common biofluid used in metabolomics; however, since extracellular vesicles (EVs) hold cell-specific biological material and can cross the blood-brain barrier, their utilization as biological material warrants further investigation. We aimed to investigate blood- and EV-derived metabolites to add insigts to the pathological mechanisms of AD. METHODS: Blood samples were collected from 10 AD and 10 Mild Cognitive Impairment (MCI) patients, and 10 healthy controls. EVs were enriched from plasma using 100,000×g, 1 h, 4 °C with a wash. Metabolites from serum and EVs were measured using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy. Multivariate and univariate analyses were employed to identify altered metabolites in cognitively impaired individuals. RESULTS: While no significant EV-derived metabolites were found differentiating patients from healthy individuals, six serum metabolites were found important; valine (p = 0.001, fold change, FC = 0.8), histidine (p = 0.001, FC = 0.9), allopurinol riboside (p = 0.002, FC = 0.2), inosine (p = 0.002, FC = 0.3), 4-pyridoxic acid (p = 0.006, FC = 1.6), and guanosine (p = 0.004, FC = 0.3). Pathway analysis revealed branched-chain amino acids, purine and histidine metabolisms to be downregulated, and vitamin B6 metabolism upregulated in patients compared to controls. CONCLUSION: Using a combination of LC-MS and NMR methodologies we identified several altered mechanisms possibly related to AD pathology. EVs require additional optimization prior to their possible utilization as a biological material for AD-related metabolomics studies.
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Alzheimer's disease (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics; however, comprehensive plasma profiling is challenging due to the dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood-brain barrier and may provide a source for AD biomarkers. We investigated plasma-derived EV proteins for AD biomarkers from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The ultracentrifuged EVs were washed and confirmed according to the MISEV2018 guidelines. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67-1.00) with ORM2 (AUC: 1.00, CI: 1.00-1.00), RBP4 (AUC: 0.99, CI: 0.95-1.00), and HYDIN (AUC: 0.89, CI: 0.72-1.00) were found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible AD biomarkers. Some of the MCI patients, with similar protein profiles as the AD group, progressed to AD within a 2-year timespan.
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Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva/metabolismo , Vesículas Extracelulares/metabolismo , Anciano , Biomarcadores/metabolismo , Coagulación Sanguínea/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , ProteómicaRESUMEN
BACKGROUND: Small cell lung cancer (SCLC) is a malignant disease with poor prognosis. At the time of diagnosis most patients are already in a metastatic stage. Current diagnosis is based on imaging, histopathology, and immunohistochemistry, but no blood-based biomarkers have yet proven to be clinically successful for diagnosis and screening. The precise mechanisms of SCLC are not fully understood, however, several genetic mutations, protein and metabolic aberrations have been described. We aim at identifying metabolite alterations related to SCLC and to expand our knowledge relating to this aggressive cancer. METHODS: A total of 30 serum samples of patients with SCLC, collected at the time of diagnosis, and 25 samples of healthy controls were included in this study. The samples were analyzed with nuclear magnetic resonance spectroscopy. Multivariate, univariate and pathways analyses were performed. RESULTS: Several metabolites were identified to be altered in the pre-treatment serum samples of small-cell lung cancer patients compared to healthy individuals. Metabolites involved in tricarboxylic acid cycle (succinate: fold change (FC) = 2.4, p = 0.068), lipid metabolism (LDL triglyceride: FC = 1.3, p = 0.001; LDL-1 triglyceride: FC = 1.3, p = 0.012; LDL-2 triglyceride: FC = 1.4, p = 0.009; LDL-6 triglyceride: FC = 1.5, p < 0.001; LDL-4 cholesterol: FC = 0.5, p = 0.007; HDL-3 free cholesterol: FC = 0.7, p = 0.002; HDL-4 cholesterol FC = 0.8, p < 0.001; HDL-4 apolipoprotein-A1: FC = 0.8, p = 0.005; HDL-4 apolipoprotein-A2: FC ≥ 0.7, p ≤ 0.001), amino acids (glutamic acid: FC = 1.7, p < 0.001; glutamine: FC = 0.9, p = 0.007, leucine: FC = 0.8, p < 0.001; isoleucine: FC = 0.8, p = 0.016; valine: FC = 0.9, p = 0.032; lysine: FC = 0.8, p = 0.004; methionine: FC = 0.8, p < 0.001; tyrosine: FC = 0.7, p = 0.002; creatine: FC = 0.9, p = 0.030), and ketone body metabolism (3-hydroxybutyric acid FC = 2.5, p < 0.001; acetone FC = 1.6, p < 0.001), among other, were found deranged in SCLC. CONCLUSIONS: This study provides novel insight into the metabolic disturbances in pre-treatment SCLC patients, expanding our molecular understanding of this malignant disease.
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Small cell lung cancer (SCLC) patients have augmented risk of developing venous thromboembolism, but the mechanisms triggering this burden on the coagulation system remain to be understood. Recently, cell-derived microparticles carrying procoagulant phospholipids (PPL) and tissue factor (TF) in their membrane have attracted attention as possible contributors to the thrombogenic processes in cancers. The aims of this study were to assess the coagulation activity of platelet-poor plasma from 38 SCLC patients and to provide a detailed procoagulant profiling of small and large extracellular vesicles (EVs) isolated from these patients at the time of diagnosis, during and after treatment compared to 20 healthy controls. Hypercoagulability testing was performed by thrombin generation (TG), procoagulant phospholipid (PPL), TF activity, Protein C, FVIII activity and cell-free deoxyribonucleic acid (cfDNA), a surrogate measure for neutrophil extracellular traps (NETs). Our results revealed a coagulation activity that is significantly increased in the plasma of SCLC patients when compared to age-related healthy controls, but no substantial changes in coagulation activity during treatment and at follow-up. Although EVs in the patients revealed an increased PPL and TF activity compared with the controls, the TG profiles of EVs added to a standard plasma were similar for patients and controls. Finally, we found no differences in the coagulation profile of patients who developed VTE to those who did not, i.e. the tests could not predict VTE. In conclusion, we found that SCLC patients display an overall increased coagulation activity at time of diagnosis and during the disease, which may contribute to their higher risk of VTE.
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Carcinoma de Células Pequeñas/sangre , Cisteína Endopeptidasas/sangre , Neoplasias Pulmonares/sangre , Proteínas de Neoplasias/sangre , Trombofilia/sangre , Tromboplastina/análisis , Adulto , Anciano , Anciano de 80 o más Años , Pruebas de Coagulación Sanguínea , Carcinoma de Células Pequeñas/etiología , Carcinoma de Células Pequeñas/patología , Centrifugación , ADN/sangre , Vesículas Extracelulares/química , Vesículas Extracelulares/ultraestructura , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Masculino , Microscopía Inmunoelectrónica , Persona de Mediana Edad , Nanopartículas , Embolia Pulmonar/sangre , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Factores de Riesgo , Trombina/biosíntesis , Trombofilia/etiología , Tromboembolia Venosa/sangre , Tromboembolia Venosa/etiologíaRESUMEN
BACKGROUND: Multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of thrombotic events, especially during anti-myeloma treatment. Many different underlying causes for this hypercoagulability have been suggested, but current techniques to identify abnormalities in these patients are sparse and inefficient. The aim of this study was to assess the hypercoagulability in MGUS and MM patients through various coagulation analyses and identify changes in the MM patients throughout their treatment regimen. MATERIALS AND METHODS: Platelet-free plasma from 38 MM patients, 19 MGUS patients and 34 healthy controls were tested for hypercoagulability using calibrated automated thrombogram, a procoagulant phospholipid assay, a microvesicle-associated (MV) tissue factor (TF) assay, and a cell-free deoxyribonucleic acid (cf-DNA) assay as a surrogate measurement for neutrophil extracellular traps (NETs). RESULTS: MGUS and MM patients both had elevated thrombin generation and procoagulant phospholipid activity in comparison to the control subjects. MM, and partly MGUS, showed increased MV-TF activity, however, only MM had increased levels of the cf-DNA. CONCLUSIONS: Here we demonstrated that hypercoagulability was present in patients with MGUS and MM through increased thrombin generation, possibly due to higher TF and procoagulant phospholipids (PPL) activity. This may be associated to MVs and, for MM patients, be attributed to procoagulant NETs activity; however, this remains to be determined.