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Minimally invasive transcatheter interventional therapy utilizing cardiac occluders represents the primary approach for addressing congenital heart defects and left atrial appendage (LAA) thrombosis. However, incomplete endothelialization and delayed tissue healing after occluder implantation collectively compromise clinical efficacy. In this study, we have customized a recombinant humanized collagen type I (rhCol I) and developed an rhCol I-based extracellular matrix (ECM)-mimetic coating. The innovative coating integrates metal-phenolic networks with anticoagulation and anti-inflammatory functions as a weak cross-linker, combining them with specifically engineered rhCol I that exhibits high cell adhesion activity and elicits a low inflammatory response. The amalgamation, driven by multiple forces, effectively serves to functionalize implantable materials, thereby responding positively to the microenvironment following occluder implantation. Experimental findings substantiate the coating's ability to sustain a prolonged anticoagulant effect, enhance the functionality of endothelial cells and cardiomyocyte, and modulate inflammatory responses by polarizing inflammatory cells into an anti-inflammatory phenotype. Notably, occluder implantation in a canine model confirms that the coating expedites reendothelialization process and promotes tissue healing. Collectively, this tailored ECM-mimetic coating presents a promising surface modification strategy for improving the clinical efficacy of cardiac occluders.
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Materiales Biocompatibles Revestidos , Matriz Extracelular , Cicatrización de Heridas , Animales , Matriz Extracelular/metabolismo , Perros , Humanos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Colágeno Tipo I/metabolismo , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Células Endoteliales de la Vena Umbilical Humana , Repitelización/efectos de los fármacos , Adhesión Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Thrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. AIM OF THE STUDY: This work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. MATERIALS AND METHODS: Systematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. RESULTS: A total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3ß-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than -5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. CONCLUSION: Our integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.
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Fibrinolíticos , Metabolómica , Simulación del Acoplamiento Molecular , Farmacología en Red , Ratas Sprague-Dawley , Trombosis , Animales , Fibrinolíticos/farmacología , Fibrinolíticos/química , Fibrinolíticos/aislamiento & purificación , Ratas , Masculino , Trombosis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/químicaRESUMEN
Sour bamboo shoots are a traditional fermented delicacy that has garnered appreciation both domestically and internationally. This study investigates the intricate dynamics of microbial communities and volatile flavor compounds primarily derived from salted and pickled bamboo shoots during the fermentation process of Phyllostachys purpurea (PP). The dynamics of microorganisms and volatile flavor compounds were thoroughly examined initially using conventional isolation and cultivation methods in conjunction with high-throughput sequencing (HTS), headspace solid-phase microextraction (HS-SPME), and gas chromatography-mass spectrometry (GC-MS). In addition, we analyzed the core microorganisms responsible for modulating the volatile flavor profile. Our findings revealed 60 volatile compounds, 14 of which were the predominant contributors to the aroma of fermented PP. This group primarily comprised alcohols, aldehydes, and olefins. Notably, our investigation identified Lactobacillus and Candida as the dominant microbial genera during the middle and late stages of fermentation. These two genera exert a significant influence on the formation of characteristic aromas. Furthermore, we discovered that acids, sugars, and proteins pivotally influence the succession of microorganisms. Specifically, acids and soluble sugars drove the transition of Lactococcus to Lactobacillus and Pediococcus, whereas soluble proteins facilitated fungal succession from Candida to Kazachstania and Issatchenkia. These insights shed light on the community structure and succession patterns of flavor compounds throughout the PP fermentation process. Ultimately, they provide a foundation for optimizing the fermentation process and ensuring quality control in the production of sour bamboo shoots.
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Bacterias , Fermentación , Microbiota , Brotes de la Planta , Compuestos Orgánicos Volátiles , Compuestos Orgánicos Volátiles/análisis , Compuestos Orgánicos Volátiles/metabolismo , Brotes de la Planta/química , Brotes de la Planta/microbiología , Brotes de la Planta/metabolismo , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética , Bacterias/aislamiento & purificación , Cromatografía de Gases y Espectrometría de Masas , Hongos/metabolismo , Hongos/clasificación , Hongos/aislamiento & purificación , Hongos/genética , Aromatizantes/metabolismo , Alimentos Fermentados/microbiología , Alimentos Fermentados/análisis , Odorantes/análisis , Bambusa/microbiología , Bambusa/metabolismo , Bambusa/química , Microextracción en Fase SólidaRESUMEN
In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists.
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Aprobación de Drogas , United States Food and Drug Administration , Estados Unidos , Humanos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/síntesis químicaRESUMEN
The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom-derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX-III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore-guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1-SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1-SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off-target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7-specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications.
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Urinary system stones are a common clinical disease, with significant differences in incidence and recurrence rates between different countries and regions. The etiology and pathogenesis of urinary system stones have not been fully elucidated, but many studies have found that some bacteria and fungi that are difficult to detect in urine constitute a unique urinary microbiome. This special urinary microbiome is closely related to the occurrence and development of urinary system stones. By analyzing the urinary microbiome and its metabolic products, early diagnosis and treatment of urinary system stones can be carried out. This article reviews the relationship between the urinary microbiome and urinary system stones, discusses the impact of the microbiome on the formation of urinary system stones and its potential therapeutic value, with the aim of providing a reference for the early diagnosis, prevention, and treatment of urinary system stones.
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Kidney Stone Disease (KSD) constitutes a multifaceted disorder, emerging from a confluence of environmental and genetic determinants, and is characterized by a high frequency of occurrence and recurrence. Our objective is to elucidate potential causative proteins and identify prospective pharmacological targets within the context of KSD. This investigation harnessed the unparalleled breadth of plasma protein and KSD pooled genome-wide association study (GWAS) data, sourced from the United Kingdom Biobank Pharma Proteomics Project (UKBPPP) and the FinnGen database version R10. Through Mendelian randomization analysis, proteins exhibiting a causal influence on KSD were pinpointed. Subsequent co-localization analyses affirmed the stability of these findings, while enrichment analyses evaluated their potential for pharmacological intervention. Culminating the study, a phenome-wide association study (PheWAS) was executed, encompassing all phenotypes (2408 phenotypes) catalogued in the FinnGen database version R10. Our MR analysis identified a significant association between elevated plasma levels of proteins FKBPL, ITIH3, and SERPINC1 and increased risk of KSD based on genetic predictors. Conversely, proteins CACYBP, DAG1, ITIH1, and SEMA6C showed a protective effect against KSD, documented with statistical significance (PFDR<0.05). Co-localization analysis confirmed these seven proteins share genetic variants with KSD, signaling a shared genetic basis (PPH3 + PPH4 > 0.8). Enrichment analysis revealed key pathways including hyaluronan metabolism, collagen-rich extracellular matrix, and serine-type endopeptidase inhibition. Additionally, our PheWAS connected the associated proteins with 356 distinct diseases (PFDR<0.05), highlighting intricate disease interrelations. In conclusion, our research elucidated a causal nexus between seven plasma proteins and KSD, enriching our grasp of prospective therapeutic targets.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteoma , Humanos , Nefrolitiasis/genética , Nefrolitiasis/sangre , Nefrolitiasis/metabolismo , Fenotipo , ProteómicaRESUMEN
In this study, the potential mechanism of aroma loss in non-smoked bacon due to excessive hot air drying (beyond 24 h) was investigated, focusing on protein conformational changes and the inhibition of heme protein-mediated lipid oxidation by oleic acid. The results showed that prolonged hot-air drying caused a stretching of the myofibrillar protein (MP) conformation in bacon before 36 h, leading to an increase in reactive sulfhydryl groups, surface hydrophobicity, and the exposure of additional hydrophobic sites. Consequently, the binding ability of MP to the eight key aroma compounds (hexanal, 1-octen-3-ol, (E)-2-nonenal, 3-methyl-butanoic acid, 2-undecenal, (E, E)-2,4-decadienal, 2,3-octanedione, and dihydro-5-pentyl-2(3H)-furanone) was enhanced, resulting in their retention. On the other hand, a sustained increase in oleic acid levels has been demonstrated to effectively inhibit heme protein-mediated lipid oxidation and the formation of these key aroma compounds. Using lipidomic techniques, 30 lipid molecules were identified as potential precursors of oleic acid during the bacon drying process. Among these precursors, triglycerides (16:0/18:0/18:1) may be the most significant.
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Calor , Odorantes , Odorantes/análisis , Desecación/métodos , Productos de la Carne/análisis , Ácido Oléico/química , Manipulación de Alimentos/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Conformación Proteica , Compuestos Orgánicos Volátiles/análisis , Compuestos Orgánicos Volátiles/química , Oxidación-Reducción , Aldehídos/análisis , Aldehídos/químicaRESUMEN
Low temperature (LT) in spring usually occurs at the booting of winter wheat, resulting in reduction of wheat yield. In this study, we used the LT-sensitive wheat cultivar 'Wanmai 52' and the LT-insensitive wheat cultivar 'Yannong 19' as experimental materials to conduct LT treatment (-2 â and 0 â) at booting stage. After the LT treatment, we sprayed 6-benzylaminoadenine (6-BA) solutions with concentrations of 10, 20, and 30 mg·L-1 respectively, with equal mass distilled water as control to investigate the effects of spraying 6-BA on the physiological characteristics, yield and quality of wheat flag leaves after LT stress at booting stage. The results showed that compared with the control, young ear of wheat treated with exogenous spraying 6-BA was fuller, the floret morphology was improved, and the number of vascular bundles under the spike was increased. 6-BA application promoted the accumulation of soluble sugar, soluble protein, and proline in flag leaves. The activities of peroxidase and superoxide dismutase were increased, and the content of malondialdehyde was decreased. Exogenous 6-BA application decreased the number of degenerated spikes of wheat, increased the number of grains per spike and 1000-grain weight, as well as the contents of grain protein, wet gluten, and sedimentation value. In summary, exogenous 6-BA application could effectively alleviate the effects of LT stress on flag leaf and yield of wheat. Under the conditions of this experiment, the mitigation effect of spraying 6-BA solution on Yannong 19 was higher than that of Wanmai 52, and the mitigation effect of spraying 20 mg·L-1 6-BA solution on low temperature stress was the best.
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Frío , Hojas de la Planta , Purinas , Estrés Fisiológico , Triticum , Triticum/crecimiento & desarrollo , Triticum/metabolismo , Triticum/efectos de los fármacos , Triticum/fisiología , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Purinas/farmacología , Biomasa , Reguladores del Crecimiento de las Plantas/farmacología , Control de Calidad , Compuestos de BenciloRESUMEN
Rationale: Dysregulated T-cell immune response-mediated inflammation plays critical roles in the pathology of diverse liver diseases, but the underlying mechanism of liver immune homeostasis control and the specific therapies for limiting T-cell overactivation remain unclear. Methods: The metabolic changes in concanavalin A (ConA) mice and autoimmune hepatitis (AIH) patients and their associations with liver injury were analyzed. The expression of purine catabolism nucleases (e.g., CD39 and CD73) on liver cells and immune cells was assessed. The effects of MCregs and their extracellular vesicles (EVs) on CD4+ T-cell overactivation and the underlying mechanism were also explored. Results: Our findings revealed significant alterations in purine metabolism in ConA mice and AIH patients, which correlated with liver injury severity and therapeutic response. CD39 and CD73 were markedly upregulated on CD11b+Gr-1+ MCs under liver injury conditions. The naturally expanded CD39+CD73+Gr-1highCD11b+ MCreg subset during early liver injury effectively suppressed CD4+ T-cell hyperactivation and liver injury both in vitro and in vivo. Mechanistically, MCregs released CD73high EVs, which converted extracellular AMP to immunosuppressive metabolites (e.g., adenosine and inosine), activating the cAMP pathway and inhibiting glycolysis and cytokine secretion in activated CD4+ T cells. Conclusions: This study provides insights into the mechanism controlling immune homeostasis during the early liver injury phase and highlights that MCreg or MCreg-EV therapy may be a specific strategy for preventing diverse liver diseases induced by T-cell overactivation.
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Vesículas Extracelulares , Hepatitis Autoinmune , Ratones Endogámicos C57BL , Purinas , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Ratones , Purinas/metabolismo , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/metabolismo , Hepatitis Autoinmune/patología , Humanos , Apirasa/metabolismo , Hígado/metabolismo , Hígado/inmunología , Hígado/patología , Células Mieloides/metabolismo , Células Mieloides/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Masculino , 5'-Nucleotidasa/metabolismo , Activación de Linfocitos/inmunología , Concanavalina A , Femenino , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/inmunología , Antígenos CDRESUMEN
Purpose: Matrix metalloproteinase-11 (MMP11), which belongs to the stromelysin subgroup, has been reported to play a role in the progression of colorectal cancer (CRC). However, the significance of MMP11 in the tumor microenvironment, immune/stromal cells, and its mechanism in CRC remain unclear. Methods: The impact of MMP11 knockdown using specific short hairpin RNAs (shRNAs) on the metastasis and invasion of colorectal cancer RKO and SW480 cells was investigated using western blot, quantitative real-time polymerase chain reaction (qRT-PCR), transwell assays, and immunohistochemistry. Results: MMP11 mRNA expression was significantly higher in CRC cells than in normal cells, and its expression was stimulated in CCD-18Co fibroblasts. Additionally, MMP11 expression was found to be higher in individuals aged ≤ 65 years, the T4/T3 group, and Stage III/IV patients. Overall survival (OS) and disease-free survival rates were significantly different between the high and low MMP11 groups. Furthermore, the receiver operating characteristic (ROC) curves for MMP11 at 1-, 3-, and 5-years were 0.450, 0.552, and 0.560, respectively. Moreover, MMP11 promoted the migration and invasion of CRC cells by elevating the expression of Slug protein. Most importantly, MMP11 was positively associated with M0-macrophages and negatively associated with M1-macrophages, NK cells activated, NK cells resting, T cells CD4 memory activated, and T cells follicular helper, indicating the remarkable interactions of MMP11 with tumor immunology. Conclusions: MMP11 plays an important role in colorectal cancer development, and its mechanism in CRC needs to be further explored in the future.
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Movimiento Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 11 de la Matriz , Invasividad Neoplásica , Factores de Transcripción de la Familia Snail , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Metaloproteinasa 11 de la Matriz/genética , Metaloproteinasa 11 de la Matriz/metabolismo , Invasividad Neoplásica/genética , Movimiento Celular/genética , Masculino , Línea Celular Tumoral , Femenino , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Supervivencia sin EnfermedadRESUMEN
Two new indole-diterpenoids, penpaxilloids F and G (1 and 2), along with 11 known analogues (3-13), were isolated from the marine fungus Penicillium sp. ZYX-Z-718. The structures of the new compounds were identified by extensive spectroscopic analyses including HR-ESI-MS, UV, and NMR, as well as theoretical NMR chemical shifts and ECD calculations. Compounds 6 and 10 showed antibacterial activity against Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, and MRSA with MIC values ranging from 16.0 to 32.0 µg/mL.
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A new steroid named persteroid (1) and seven known compounds (2-8) were isolated from the marine-derived fungus Penicillium sp. ZYX-Z-143. The structure of 1 was determined by HRESIMS, NMR, and ECD calculations. Compound 1 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 46.31 ± 0.52 µM. Moreover, compound 1 potently suppressed nitric oxide (NO) production on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The cytotoxicity and antibacterial activity of all isolates were tested.
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Background: The occurrence of type A aortic dissection (TAAD) during transoesophageal echocardiography (TEE) has only been reported once. We present another case of pre-procedural type B AD with retrograde TAAD or de novo TAAD during the TEE procedure. Case summary: An 81-year-old man with a pre-existing infrarenal abdominal aortic aneurysm and highly tortuous aorta was referred to our ward for acute decompensated heart failure (ADHF) with New York Heart Association functional class II. On hospital Day 2, the patient complained of intermittent dull pain over chest and back; ADHF or acute coronary syndrome was suspected. On Day 3, we transferred the patient to the intensive care unit due to ADHF with cardiogenic shock attributed to fluid overload, atrial fibrillation with rapid ventricular response, and severe mitral regurgitation with severely impaired left ventricular ejection fraction. Given the heightened surgical risk, TEE was performed to evaluate the eligibility of mitral transcatheter edge-to-edge repair. The first mid-oesophageal long-axis view showed no evidence of dissection. After 20â min, the same view showed the occurrence of TAAD. Urgent contrast CT confirmed a TAAD extending from the aortic root to the infrarenal abdominal aorta. Due to the prohibitive risk for surgical repair of TAAD, the patient received palliative care and unfortunately passed away on hospital Day 6. Discussion: Albeit rare, TAAD could progress or de novo occur during TEE, especially in high-risk patients. Therefore, high alertness during TEE procedures is imperative. Moreover, in patients with AD and poor renal function, the risk of using TEE as an alternative diagnostic modality should be carefully considered.
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The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
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Sugammadex (SUG) is a novel antagonist of neuromuscular blocking agents (NMBAs). The NMBA rocuronium is usually employed to obtain better surgical conditions in kidney transplant. Nevertheless, rocuronium has several disadvantages, such as an increased risk of pulmonary complications. Thus, SUG is vital to kidney-transplant surgery. However, because SUG is excreted by the kidneys in prototypes, the pharmacokinetics (PK) may be affected in patients with renal impairment. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to monitor SUG in plasma samples to investigate the PK of SUG in kidney-transplant patients. Due to the complexity and limitation of other methods of sample preparation, magnetic solid-phase extraction (MSPE) was adopted to purify samples. Chromatographic separation was obtained using a reversed-phase Polaris® C18 column and gradient elution with 0.1% formic acid (FA) in water as phase A and in methanol (MeOH) as phase B as mobile phases. The transitions 999.7 â 963.9 (m/z) and 1055.7 â 1012.2 (m/z) were used to quantify SUG and ORG26265, respectively, under negative electrospray ionization. A linear calibration curve was achieved in concentrations varying from 100 to 10 000 ng mL-1. The acceptable accuracy varied from 95.7% to 106.4%, and intra- and inter-precision did not exceed 15% (20% at the lower limit of quantitation (LLOQ)). The matrix effect, stability, dilution integrity, and carry-over were validated. This method was applied successfully for the PK study of 13 recipients and 12 donors of kidney transplant after intravenous injection of SUG (2 mL per kg bodyweight).
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Objective: The purpose of this study is to develop and assess a nomogram risk prediction model for central precocious puberty (CPP) in obese girls. Methods: We selected 154 cases of obese girls and 765 cases of non-obese girls with precocious puberty (PP) who underwent the gonadotropin-releasing hormone stimulation test at the Jiangxi Provincial Children's Hospital. Univariate analysis and multivariate analysis were conducted to identify predictors of progression to CPP in girls with PP. A predictive model was developed and its predictive ability was preliminarily evaluated. The nomogram was used to represent the risk prediction model for CPP in girls with obesity. The model was validated internally using the Bootstrap method, and its efficacy was assessed using calibration curves and clinical decision analysis curves. Results: In obese girls with PP, basal luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, as well as uterine volume, were identified as independent risk factors for progression to CPP. In non-obese girls, the basal LH level, bone age, and uterine volume were identified as independent risk factors for progression to CPP. With an AUC of 0.896, the risk prediction model for obese girls, was found to be superior to that for non-obese girls, which had an AUC of 0.810. The model displayed strong predictive accuracy. Additionally, a nomogram was used to illustrate the CPP risk prediction model for obese girls. This model performs well in internal validation and is well calibrated, providing a substantial net benefit for clinical use. Conclusion: A medical nomogram model of CPP risk in obese girls comprised of basal LH value, basal FSH value, and uterine volume, which can be used to identify those at high risk for progression of CPP in obese girls and develop individualized prevention programs.
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BACKGROUD: Supernatants from various cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF), and needle aspiration, have been validated for detecting genetic alterations using cell-free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). However, the sensitivity of fusion variations detection remains challenging. The protection of cell-free RNA (cfRNA) is critical for resolving the issue. METHODS: A protective solution (PS) was applied for preserving cfRNA in cytological supernatant (CS), and the quality of protected cfRNA was assessed by cycle threshold (CT) values from reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, we collected an additional set of malignant cytological and matched tumor samples from 84 NSCLC patients, cfDNA & cfRNA extraction and double detection for driver gene mutations was validated using the multi-gene mutations detection by RT-qPCR. RESULTS: Under the optimal protection system, 91.0% (101/111) of cfRNA were protected effectively. Among the 84 NSCLC patient samples, seven cytological samples failed the tests. In comparison with tumor samples, the overall sensitivity and specificity of detecting driver genes of supernatant cfDNA and cfRNA were 93.8% (74/77) and 100% (77/77), respectively. Notably, when focusing exclusively on patients with fusion gene changes, both sensitivity and specificity reached 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET ex14 skipping. CONCLUSION: These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.