RESUMEN
Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal ß -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
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Carnitina , Resistencia a la Insulina , Biomarcadores , Carnitina/análogos & derivados , Carnitina/química , Carnitina/metabolismo , Carnitina/uso terapéutico , Ácidos Grasos/metabolismo , Humanos , Resistencia a la Insulina/fisiologíaRESUMEN
The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.
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Bases de Datos Genéticas , Metaboloma/genética , Metabolómica/clasificación , Humanos , Lipidómica/clasificación , Espectrometría de Masas , Interfaz Usuario-ComputadorRESUMEN
Glyphosate, a globally prevalent herbicide known for its selective inhibition of the shikimate pathway in plants, is now implicated in physiological effects on humans and animals, probably due to its impacts in their gut microbiomes which possess the shikimate pathway. In this study, we investigate the effects of environmentally relevant concentrations of glyphosate on the gut microbiota, neurotransmitter levels, and anxiety in zebrafish. Our findings demonstrate that glyphosate exposure leads to dysbiosis in the zebrafish gut, alterations in central and peripheral serotonin levels, increased dopamine levels in the brain, and notable changes in anxiety and social behavior. While the dysbiosis can be attributed to glyphosate's antimicrobial properties, the observed effects on neurotransmitter levels leading to the reported induction of oxidative stress in the brain indicate a novel and significant mode of action for glyphosate, namely the impairment of the microbiome-gut-axis. While further investigations are necessary to determine the relevance of this mechanism in humans, our findings shed light on the potential explanation for the contradictory reports on the safety of glyphosate for consumers.
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Glifosato , Herbicidas , Humanos , Animales , Pez Cebra/metabolismo , Glicina/toxicidad , Disbiosis/inducido químicamente , Ácido Shikímico/metabolismo , Herbicidas/toxicidad , NeurotransmisoresRESUMEN
OBJECTIVE: The study used both person-centered (i.e., parallel process latent class growth modeling) and variable-centered (i.e., random intercept cross-lagged panel modeling) approaches to examine developmental changes in global and domain-specific self-esteem from middle childhood to early adolescence. METHOD: A total of 715 Chinese youth participated (54.3% boys; 45.7% girls; Mage = 9.96; SD = 0.51) in a 6-wave longitudinal study with 6-month intervals. RESULTS: Parallel process latent class growth modeling identified three co-developmental trajectories of global and domain-specific self-esteem: Congruent high increasing and then flattening global and domain-specific self-esteem, congruent moderate domain-specific self-esteem with convex global self-esteem, and congruent low with concave appearance and global self-esteem. Results from random intercept cross-lagged panel modeling found reciprocal within-person associations between academic self-esteem and global self-esteem; global self-esteem significantly predicted social self-esteem, while physical appearance self-esteem significantly predicted global self-esteem. CONCLUSION: Evidence was provided for top-down and bottom-up effects of self-esteem among Chinese youth. The findings provided new insight into the development of self-esteem in youth.
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Immunosuppression plays a significant role in tumor recurrence and metastasis, ultimately causing poor survival outcomes. Overcoming immunosuppression and stimulating durable antitumor immunity are essential for tumor treatment. In our previous study, a novel cryo-thermal therapy involving liquid nitrogen freezing and radiofrequency heating could reduce the proportion of Myeloid-derived suppressor cells (MDSCs), but the remaining MDSCs produced IL-6 by the NF-κB pathway, resulting in an impaired therapeutic effect. Therefore, here we combined cryo-thermal therapy with anti-IL-6 treatment to target the MDSC-dominant immunosuppressive environment, thereby optimizing the efficacy of cryo-thermal therapy. We found that combinational treatment significantly increased the long-term survival rate of breast cancer-bearing mice. Mechanistic investigation revealed that combination therapy was capable of reducing the proportion of MDSCs in the spleen and blood while promoting their maturation, which resulted in increased Th1-dominant CD4+ T-cell differentiation and enhancement of CD8+ T-mediated tumor killing. In addition, CD4+ Th1 cells promoted mature MDSCs to produce IL-7 through IFN-γ, indirectly contributing to the maintenance of Th1-dominant antitumor immunity in a positive feedback loop. Our work suggests an attractive immunotherapeutic strategy targeting the MDSC-dominant immunosuppressive environment, which would offer exciting opportunities for highly immunosuppressive and unresectable tumors in the clinic.
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Células Supresoras de Origen Mieloide , Animales , Ratones , Recurrencia Local de Neoplasia , Modelos Animales de Enfermedad , Células TH1 , Terapia CombinadaRESUMEN
BACKGROUND: Lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). Recent studies have indicated that statins tend to increase Lp(a) levels by 10-20%. However, the association of statin-mediated increases in Lp(a) levels with CAD has not been determined. METHODS: This study included 488 patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Lp(a) levels were measured at baseline and 1 month after statin therapy. The study endpoints were major adverse cardiovascular events (MACE). Hazard ratios for the MACE were adjusted for potential confounder using Cox regression. RESULTS: After statin therapy, the mean level of Lp(a) increased by 19.3% from baseline. Lp(a) levels increased in 307 patients (62.9%) with a median elevation of 4.1 mg/dL. Patients with an increase in Lp(a) were at higher risk for MACE than those without an increase in Lp(a) (p = 0.044). Subgroup analyses revealed that a mild-to-moderate increase in Lp(a) was not associated with MACE, whereas there was a strong correlation between the highest quartile increase in Lp(a) (≥ 10.1 mg/dL) and MACE (HR = 2.29, 95%CI = 1.36-3.84, p = 0.002). This correlation was independent of baseline Lp(a) levels but not independent of on-statin Lp(a) levels. CONCLUSIONS: Severe increases in Lp(a) following statin therapy raise the risk of MACE, but a mild-to-moderate increase in Lp(a) may not affect the cardiovascular prognosis of CAD patients. Even if the baseline Lp(a) levels are low, it is necessary to continue testing for Lp(a) concentration at least once after statin.
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Enfermedad de la Arteria Coronaria , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Intervención Coronaria Percutánea , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Prevención Secundaria , Lipoproteína(a) , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Lipoprotein(a) [Lp(a)] elevation is an important risk factor for coronary artery disease (CAD). However, the correlation between Lp(a) elevations and the risk of recurrent cardiovascular events in patients with established cardiovascular disease is controversial. Some studies have shown that Low-density lipoprotein cholesterol (LDL-C) levels may influence the association between Lp(a) and cardiovascular risk. Our study aims to explore the correlation between Lp(a) elevations and cardiovascular risk in patients with different LDL-C levels. METHODS: We included 516 patients who received coronary stents due to acute coronary syndrome (ACS) and followed them for three years. They were divided into low-Lp(a) group and high-Lp(a) group according to Lp(a) levels, and the incidence of major adverse cardiovascular events (MACE) and acute coronary events (ACE) was compared between the two groups. Then the patients were divided into three subgroups (S1:LDL-C ≥ 1.8 mmol/L; S2:1.4 ≤ LDL-C < 1.8 mmol/L; S3:LDL-C < 1.4 mmol/L). The correlation between Lp(a) elevations and cardiovascular risk in different subgroups was analysed by Cox proportional hazards models. RESULTS: The incidence of MACE and ACE in the high-Lp(a) group was significantly higher than those in the low-Lp(a) group (P < 0.05). Lp(a) elevations had independent prognostic value from the statistical point of view (MACE: HR = 1.63, 95%CI = 1.12-2.38, P = 0.012; ACE: HR = 1.70, 95%CI = 1.03-2.81, P = 0.037). Subgroup analysis showed that Lp(a) elevations increased cardiovascular risk when LDL-C ≥ 1.4 mmol/L. However, this correlation no longer existed when LDL-C levels were very low (< 1.4 mmol/L) (MACE: HR = 0.49, 95%CI = 0.17-1.42, P = 0.186; ACE: HR = 0.68, 95%CI = 0.18-2.61, P = 0.570). CONCLUSIONS: Lp(a) elevations are associated with recurrent cardiovascular events when LDL-C levels are high, but this association may change when LDL-C levels are extremely low. CAD patients with combination of LDL-C ≥ 1.4 mmol/L and Lp(a) elevations shall be considered as high-risk groups and require further medication for the reduction of their LDL-C levels.
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Síndrome Coronario Agudo , LDL-Colesterol , Enfermedad de la Arteria Coronaria , Lipoproteína(a) , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/metabolismo , Síndrome Coronario Agudo/terapia , LDL-Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Humanos , Lipoproteína(a)/metabolismo , Factores de RiesgoRESUMEN
Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods.
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Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Algoritmos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X/métodosRESUMEN
Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, and which exhibit increased target and tissue selectivity with the aim of increasing their therapeutic index.
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Enfermedades Autoinmunes/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Enfermedades Autoinmunes/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Chronic and dysregulated cytokine signaling plays an important role in the pathogenic development of many autoimmune and inflammatory diseases. Despite intrinsic challenges in the disruption of interactions between cytokines and cytokine receptors, many first-in-class small-molecule inhibitors have been discovered over the past few years. The third part of the digest series presents recent progress in identifying such inhibitors and highlights the application of novel research tools in the fields of structural biology, computational analysis, screening methods, biophysical/biochemical assays and medicinal chemistry strategy.
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Enfermedades Autoinmunes/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Receptores de Citocinas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Enfermedades Autoinmunes/inmunología , Citocinas/inmunología , Humanos , Inflamación/inmunología , Estructura Molecular , Receptores de Citocinas/inmunología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Among all the human biological fluids used for disease biomarker discovery or clinical chemistry, urine stands out. It can be collected easily and noninvasively, it is readily available in large volumes, it is typically free from protein contamination, and it is chemically complex-reflecting a wide range of physiological states and functions. However, the comprehensive metabolomic analysis of urine has been somewhat less studied compared to blood. Indeed, most published metabolomic assays are specifically optimized for serum or plasma. In an effort to improve this situation, we have developed a comprehensive, quantitative MS-based assay for urine analysis. The assay robustly detects and quantifies 142 urinary metabolites including 28 amino acids and derivatives, 17 organic acids, 22 biogenic amines and derivatives, 40 acylcarnitines, 34 lipids, and glucose/hexose, among which 67 metabolites are absolutely quantified and 75 metabolites are semiquantified. All the analysis methods in this assay are based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) using both positive and negative-mode multiple reaction monitoring (MRM). The recovery rates of spiked urine samples at three different concentration levels, that is, low, medium and high, are in the range of 80% to 120% with satisfactory precision values of less than 20%. This targeted metabolomic assay has been successfully applied to the analysis of large numbers of human urine samples, with results closely matching those reported in the literature as well as those obtained from orthogonal analysis via NMR spectroscopy. Moreover, the assay was specifically developed in a 96-well plate format, which enables automated, high-throughput sample analysis. The assay has already been used to analyze more than 1800 urine samples in our laboratory since early 2019.
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Metabolómica/métodos , Urinálisis/métodos , Métodos Analíticos de la Preparación de la Muestra , CalibraciónRESUMEN
A chitinase gene from Serratia marcescens was cloned and expressed in Escherichia coli BL21(DE3) and the properties of recombinant chitinase rCHI-2 were characterized. The optimum catalytic pH of rCHI-2 was 6.0. It was stable in the pH range of 6.0-9.0 and could maintain more than 90% of its relative enzyme activity after incubation at 37 °C for 1 h. The optimum catalytic temperature of the enzyme was 55 °C and 85% of enzyme activity was remained after incubation at 45 °C for 1 h. The activation energy of the thermal inactivation of the enzyme was 10.9 kJ/mol and the Michaelis-Menten constant was 3.2 g/L. The purified rCHI-2 was found to be highly stable at 45 °C with half-life (t1/2) of 289 min and thermodynamic parameters ΔH*, ΔG* and ΔS* revealed high affinity of rCHI-2 for chitin. Hg2+ was found to be able to inhibit the enzyme activity reversibly, while IC50 and inhibition constant of Hg2+ on the enzyme were 34.8 µmol/L and 44.6 µmol/L, respectively. Moreover, rCHI-2 could specifically hydrolyze colloidal chitin into GlcNAc2 as the major product.
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Proteínas Bacterianas , Quitinasas , Expresión Génica , Serratia marcescens , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Quitinasas/biosíntesis , Quitinasas/química , Quitinasas/genética , Quitinasas/aislamiento & purificación , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Serratia marcescens/enzimología , Serratia marcescens/genéticaRESUMEN
A challenge facing metabolomics in the analysis of large human cohorts is the cross-laboratory comparability of quantitative metabolomics measurements. In this study, 14 laboratories analyzed various blood specimens using a common experimental protocol provided with the Biocrates AbsoluteIDQ p400HR kit, to quantify up to 408 metabolites. The specimens included human plasma and serum from male and female donors, mouse and rat plasma, as well as NIST SRM 1950 reference plasma. The metabolite classes covered range from polar (e.g., amino acids and biogenic amines) to nonpolar (e.g., diacyl- and triacyl-glycerols), and they span 11 common metabolite classes. The manuscript describes a strict system suitability testing (SST) criteria used to evaluate each laboratory's readiness to perform the assay, and provides the SST Skyline documents for public dissemination. The study found approximately 250 metabolites were routinely quantified in the sample types tested, using Orbitrap instruments. Interlaboratory variance for the NIST SRM-1950 has a median of 10% for amino acids, 24% for biogenic amines, 38% for acylcarnitines, 25% for glycerolipids, 23% for glycerophospholipids, 16% for cholesteryl esters, 15% for sphingolipids, and 9% for hexoses. Comparing to consensus values for NIST SRM-1950, nearly 80% of comparable analytes demonstrated bias of <50% from the reference value. The findings of this study result in recommendations of best practices for system suitability, quality control, and calibration. We demonstrate that with appropriate controls, high-resolution metabolomics can provide accurate results with good precision across laboratories, and the p400HR therefore is a reliable approach for generating consistent and comparable metabolomics data.
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Aminoácidos/sangre , Aminas Biogénicas/sangre , Análisis Químico de la Sangre/estadística & datos numéricos , Lipidómica/estadística & datos numéricos , Lípidos/sangre , Metabolómica/estadística & datos numéricos , Análisis de Varianza , Animales , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Agregación de Datos , Femenino , Humanos , Límite de Detección , Masculino , Espectrometría de Masas/estadística & datos numéricos , Metaboloma , Ratones , Ratas , Reproducibilidad de los ResultadosRESUMEN
The presence of ascorbate in human urine has been shown to be a useful dietary, fruit or vitamin C intake biomarker. More recently it has been discovered that ascorbate levels in urine can be used to facilitate the detection of precancerous colorectal polyps. While there are a number elaborate HPLC, MS or multi-step enzymatic "kit" methods to detect and quantify urinary ascorbate, these are time consuming and expensive. There are also a number of low-cost paper-based ascorbate detection dipsticks. However, the limits of detection and quantification accuracy for these dipsticks are not adequate for applications with human urine. To address these limitations, we have developed a fast, sensitive, single-step colorimetric assay that can be used to quantify ascorbate in urine and other biological fluids. The assay uses the tetrazolium salt, methylthiazolyldiphenyl-tetrazolium bromide (MTT), with the electron carrier phenazine methosulfate (PMS), in a chelated acidic phosphate-buffer to produce a vivid purple color in the presence of ascorbate. Confirmation of the performance of the assay and of its standard curve in human urine was also done using independent LC-MS/MS and NMR analyses. The lower limit of detection of the ascorbate dipstick assay described here was found to be 3.2⯵M. The paper dipsticks are stable over a wide range of temperatures and can be stored for up to 150-days.
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Ácido Ascórbico/orina , Colorimetría/métodos , Voluntarios Sanos , Humanos , Metosulfato de Metilfenazonio/química , Sales de Tetrazolio/químicaRESUMEN
Negatively charged nucleic acids are often complexed with polycationic transfection agents before delivery. Herein, we demonstrate that a noncationic, biocompatible polymer, polyethylene glycol, can be used as a transfection vector by forming a brush polymer-DNA conjugate. The brush architecture provides embedded DNA strands with enhanced nuclease stability and improved cell uptake. Because of the biologically benign nature of the polymer component, no cytotoxicity was observed. This approach has the potential to address several long-lasting challenges in oligonucleotide therapeutics.
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ADN sin Sentido/química , ADN sin Sentido/genética , Polietilenglicoles/química , Transfección , Secuencia de Bases , Línea Celular Tumoral , Humanos , Modelos Moleculares , Conformación de Ácido NucleicoRESUMEN
A spindle cell lipoma (SCL) is a relatively common tumor that can be challenging to the radiologist, pathologist, or surgeon to diagnose, particularly when internal fat content is scant or absent. Although these lesions may be found at various locations, the typical presentation for this lesion is a well-circumscribed and non-aggressive subcutaneous mass in the posterior neck presenting in a middle-aged to elderly man. In this article, the typical and atypical imaging characteristics of a spindle cell lipoma (SCL) will be reviewed. Knowledge of the common imaging and pathologic features of SCLs can help suggest the diagnosis and guide patient management.
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Lipoma/diagnóstico , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Tomografía Computarizada por Rayos X/métodos , HumanosRESUMEN
The prognosis for patients with colorectal cancer (CRC) remains worse than expected due to metastasis, recurrence, and resistance to chemotherapy. Colorectal cancer stem cells (CRCSCs) play a vital role in tumor metastasis, recurrence, and chemotherapy resistance. However, there are currently no prognostic markers based on CRCSCs-related genes available for clinical use. In this study, single-cell transcriptome sequencing was employed to distinguish cancer stem cells (CSCs) in the CRC microenvironment and analyze their properties at the single-cell level. Subsequently, data from TCGA and GEO databases were utilized to develop a prognostic risk model for CRCSCs-related genes and validate its diagnostic performance. Additionally, functional enrichment, immune response, and chemotherapeutic drug sensitivity of the relevant genes in the risk model were investigated. Lastly, the key gene RPS17 in the risk model was identified as a potential prognostic marker and therapeutic target for further comprehensive studies. Our findings provide new insights into the prognostic treatment of CRC and offer novel perspectives for a systematic and comprehensive understanding of CRC development.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Células Madre Neoplásicas , RNA-Seq , Análisis de la Célula Individual , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Análisis de la Célula Individual/métodos , Pronóstico , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral/genética , Transcriptoma , Perfilación de la Expresión Génica , Análisis de Secuencia de ARN/métodosRESUMEN
BACKGROUND: The drug coated balloon is a promising endovascular therapy for intracranial atherosclerosis (ICAS), potentially combining the advantages of primary angioplasty and antiproliferative drugs. Previous studies have focused on the paclitaxel coated balloon, revealing promising outcomes in the treatment of ICAS, while concerns about the neurotoxicity of paclitaxel were reported. Sirolimus was shown to have less neurotoxicity in the canine cerebral vasculature. The feasibility and safety of a sirolimus coated balloon (SCB) for ICAS have never been evaluated in humans. We assessed the first-in-human feasibility and safety of SCBs for treating symptomatic patients with severe ICAS. METHODS: This prospective, open label, single arm cohort study was designed to enroll patients with transient ischemic attacks or non-disabling, non-perforator territory ischemic stroke caused by severe ICAS (70-99%) and following at least 3 weeks after the onset of ischemic symptoms. The primary outcome was stroke or death within 30 days. All patients were followed up to detect restenosis at 6 months. RESULTS: A total of 60 eligible patients were enrolled with an average age of 59.4±10.8 years. The technical success rate of SCBs for ICAS was 100%. Seven patients (11.7%) required stenting because of flow limited dissections or elastic retraction. Three patients (5.0%) had 30 day strokes, including two ischemic strokes and one hemorrhagic stroke. An additional three patients had recurrent stroke or death during follow-up. Ten patients had restenosis but only two had symptoms. CONCLUSIONS: SCBs may be feasible and safe in selected patients with symptomatic ICAS, with high grade stenosis (70-99%). Further studies are warranted.
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Maternal pathological conditions such as infections and chronic diseases, along with unexpected events during labor, can lead to life-threatening perinatal outcomes. These outcomes can have irreversible consequences throughout an individual's entire life. Urinary metabolomics can provide valuable insights into early physiological adaptations in healthy newborns, as well as metabolic disturbances in premature infants or infants with birth complications. In the present study, we measured 180 metabolites and metabolite ratios in the urine of 13 healthy (hospital-discharged) and 38 critically ill newborns (admitted to the neonatal intensive care unit (NICU)). We used an in-house-developed targeted tandem mass spectrometry (MS/MS)-based metabolomic assay (TMIC Mega) combining liquid chromatography (LC-MS/MS) and flow injection analysis (FIA-MS/MS) to quantitatively analyze up to 26 classes of compounds. Average urinary concentrations (and ranges) for 167 different metabolites from 38 critically ill NICU newborns during their first 24 h of life were determined. Similar sets of urinary values were determined for the 13 healthy newborns. These reference data have been uploaded to the Human Metabolome Database. Urinary concentrations and ranges of 37 metabolites are reported for the first time for newborns. Significant differences were found in the urinary levels of 44 metabolites between healthy newborns and those admitted at the NICU. Metabolites such as acylcarnitines, amino acids and derivatives, biogenic amines, sugars, and organic acids are dysregulated in newborns with bronchopulmonary dysplasia (BPD), asphyxia, or newborns exposed to SARS-CoV-2 during the intrauterine period. Urine can serve as a valuable source of information for understanding metabolic alterations associated with life-threatening perinatal outcomes.