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Anaprazole is a proton pump inhibitor. This study aims to elucidate absorption, metabolism, and excretion pathways of anaprazole sodium in the human body. A total of 4 healthy Chinese male subjects were administered a single oral dose of 20 mg/100 µCi of [14C]-anaprazole sodium enteric-coated capsules. The whole blood, plasma, and excreta were analyzed for a total radioactivity (TRA) and metabolite profile. The cumulative radioactivity excretion rate was 93.2%, with 53.3% and 39.9% of the radioactive dose excreted in urine and feces, respectively, and 91.6% of dose recovered within 96 hours after dosing. The parent drug, anaprazole, showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism. Overall, 35 metabolites were identified in plasma, urine, and fecal samples. Anaprazole was the most abundant component in plasma followed by the thioether M8-1, accounting for 28.3% and 16.6%, respectively, of the plasma TRA. Thioether carboxylic acid XZP-3409 (26.3% of urine TRA) and XZP-3409 oxidation and dehydrogenation product M417a (15.1% of fecal TRA) were the major metabolites present in urine and feces, respectively. Anaprazole was undetectable in urine, while fecal samples showed traces (0.07% dose). Blood/plasma ratios of the radioactivity (approximately 0.60) remained consistent over time. Anaprazole showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism, and cytochrome P450 3A4 also contributed to its metabolism in healthy individuals.
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Urinary extracellular vesicles (uEVs) are rich in valuable biomolecule information which are increasingly recognized as potential biomarkers for various diseases. uEV long RNAs are among the critical cargos capable of providing unique transcriptome information of the source cells. However, consensus regarding ideal reference genes for relative long RNAs quantification in uEVs is not available as of date. Here we explored stable reference genes through profiling the long RNA expression by RNA-seq following unsupervised analysis and validation studies. Candidate reference genes were identified using four algorithms: NormFinder, GeNorm, BestKeeper and the Delta Ct method, followed by validation. RNA profile showed uEVs contained abundant long RNAs information and the core transcriptome was related to cellular structures, especially ribosome which functions mainly as translation, protein and RNA binding molecules. Analysis of RNA-seq data identified RPL18A, RPL11, RPL27, RACK1, RPSA, RPL41, H1-2, RPL4, GAPDH, RPS27A as candidate reference genes. RT-qPCR validation revealed that RPL41, RPSA and RPL18A were reliable reference genes for long RNA quantification in uEVs from patients with diabetes mellitus (DM), diabetic nephropathy (DN), IgA nephropathy (IgAN) and prostate cancer (PCA). Interestingly, RPL41 also outperformed traditional reference genes in renal tissues of DN and IgAN, as well as in plasma EVs of several types of cancers. The stable reference genes identified in this study may facilitate development of uEVs as novel biomarkers and increase the accuracy and comparability of biomarker studies.
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Bone metastasis is an essential factor affecting the prognosis of prostate cancer (PCa), and circulating tumor cells (CTCs) are closely related to distant tumor metastasis. Here, the protein-protein interaction (PPI) networks and Cytoscape application were used to identify diagnostic markers for metastatic events in PCa. We screened ten hub genes, eight of which had area under the ROC curve (AUC) values > 0.85. Subsequently, we aim to develop a bone metastasis-related model relying on differentially expressed genes in CTCs for accurate risk stratification. We developed an integrative program based on machine learning algorithm combinations to construct reliable bone metastasis-related genes prognostic index (BMGPI). On the basis of BMGPI, we carefully evaluated the prognostic outcomes, functional status, tumor immune microenvironment, somatic mutation, copy number variation (CNV), response to immunotherapy and drug sensitivity in different subgroups. BMGPI was an independent risk factor for disease-free survival in PCa. The high risk group demonstrated poor survival as well as higher immune scores, higher tumor mutation burden (TMB), more frequent co-occurrence mutation, and worse efficacy of immunotherapy. This study highlights a new prognostic signature, the BMGPI. BMGPI is an independent predictor of prognosis in PCa patients and is closely associated with the immune microenvironment and the efficacy of immunotherapy.
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Neoplasias Óseas , Aprendizaje Automático , Células Neoplásicas Circulantes , Neoplasias de la Próstata , Humanos , Algoritmos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Neoplasias Óseas/secundario , Neoplasias Óseas/genética , Células Neoplásicas Circulantes/patología , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Mapas de Interacción de Proteínas , Microambiente TumoralRESUMEN
Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.
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Background: The relation between mental disorders (MDs) and infertility can be reciprocal. But exactly which MD affects infertility remains controversial. Our aim was to use Mendelian randomization (MR) to explore bidirectional causality between 15 MDs and male infertility and female infertility. Methods: The data of MDs, male infertility, and female infertility were derived from published genome-wide association studies (GWAS). The inverse variance weighted method was considered to be the main analytical approach. Sensitivity analysis was performed using MR-Egger, Cochran's Q, radial MR, and MR-PRESSO tests. Results: Our results found that mood disorders (OR, 1.4497; 95% CI, 1.0093 - 2.0823; P = 0.0444) and attention deficit hyperactivity disorder (OR, 1.3921; 95% CI, 1.0943 - 1.7709; P = 0.0071) were positively correlated with male infertility, but obsessive-compulsive disorder (OR, 0.8208; 95% CI, 0.7146 - 0.9429; P = 0.0052) was negatively associated with male infertility. For females, anorexia nervosa (OR, 1.0898; 95% CI, 1.0070 - 1.1794; P = 0.0329), attention deficit hyperactivity disorder (OR, 1.1013; 95% CI, 1.0041 - 1.2079; P = 0.0406), and major depressive disorder (OR, 1.1423; 95% CI, 1.0213 - 1.2778; P = 0.0199) increased risk of infertility. In reverse relationship, female infertility increased the incidence of bipolar disorder (OR, 1.0009; 95% CI, 1.0001 - 1.0017; P = 0.0281). Conclusion: We demonstrated the association between five MDs and male or female infertility. Female infertility was also found to be associated with an increased risk of one MD. We look forward to better designed epidemiological studies to support our results.
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The regulation of seed development is critical for determining crop yield. Auxins are vital phytohormones that play roles in various aspects of plant growth and development. However, its role in amino acid biosynthesis and metabolism in seeds is not fully understood. In this study, we identified a mutant with small seeds through forward genetic screening in Medicago truncatula. The mutated gene encodes MtPIN4, an ortholog of PIN1. Using molecular approaches and integrative omics analyses, we discovered that auxin and amino acid content significantly decreased in mtpin4 seeds, highlighting the role of MtPIN4-mediated auxin distribution in amino acid biosynthesis and metabolism. Furthermore, genetic analysis revealed that the three orthologs of PIN1 have specific and overlapping functions in various developmental processes in M. truncatula. Our findings emphasize the significance of MtPIN4 in seed development and offer insights into the molecular mechanisms governing the regulation of seed size in crops. This knowledge could be applied to enhance crop quality by targeted manipulation of seed protein regulatory pathways.
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Ca-phosphate/-silicate ceramic granules have been widely studied because their biodegradable fillers can enhance bone defect repair accompanied with bioactive ion release and material degradation; however, it is a challenge to endow bioceramic composites with time-dependent ion release and highly efficient osteogenesis in vivo. Herein, we prepared dual-core-type bioceramic granules with varying chemical compositions beneficial for controlling ion release and stimulating osteogenic capability. Core-shell-structured bioceramic granules (P8-Sr4@Zn3, P8-Sr4@TCP, and P8-Sr4@HAR) composed of 8% P- and 4% Sr-substituting wollastonite (P8, Sr4) dual core components and different shell components, such as 3% Zn-substituting wollastonite (Zn3), ß-tricalcium phosphate (ß-TCP), and hardystonite (HAR), were prepared by cutting extruded core-shell fibers through dual-core ternary nozzles, followed by high-temperature sintering post-treatment. The experimental results showed that nonstoichiometric wollastonite core components contributed to more biologically active ion release in Tris buffer in vitro, and the sparingly dissolvable shell component readily maintained the granule morphology in vivo; thus, such bioceramic implants can adjust new bone growth and material degradation over time. In particular, bioceramic granules encapsulated by the TCP shell exhibited the most appreciable osteogenic capacity and expected biodegradation, which was mostly favorable for bone repair in critical bone defects. It is reasonable to consider that this new multiphasic bioceramic granule design is versatile for developing next-generation implants for various bone damage repairs.
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Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 µg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 µg/mL. Structure-activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.
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OBJECTIVE: Endothelial specific molecule-1 (ESM1) is implicated as an oncogene in multiple human cancers. However, the function of ESM1 in papillary thyroid cancer (PTC) is not well understood. The current study aimed to investigate the effect of ESM1 on the growth, migration, and invasion of PTC to provide a novel perspective for PTC treatment. METHODS: The expression levels of ESM1 in PTC tissues form 53 tumor tissue samples and 59 matching adjacent normal tissue samples were detected by immunohistochemical analysis. Knockdown of ESM1 expression in TPC-1 and SW579 cell lines was established to investigate its role in PTC. Moreover, cell proliferation, apoptosis, wound healing, and transwell assays were conducted in vitro to assess cell proliferation, migration and invasion. RESULTS: The findings revealed that ESM1 expression was significantly higher in PTC tissues than that found in paraneoplastic tissues (P<0.0001). Knockdown of ESM1 expression inhibited the proliferation, migration, and invasion of TPC-1 and SW579 cells in vitro. Compared with the control group, the mRNA and protein levels of ESM1 in PTC cells were significantly reduced following knockdown of its expression (P<0.01). In addition, ESM1-knockdown cells indicated decreased proliferation and decreased migratory and invasive activities (P<0.01, P<0.01, P<0.001, respectively). CONCLUSIONS: ESM1 was identified as a major gene in the occurrence and progression of PTC, which could increase the proliferation, migration, and invasion of PTC cells. It may be a promising diagnostic and therapeutic target gene.
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Carcinoma Papilar , MicroARNs , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , ARN Interferente Pequeño/genética , Neoplasias de la Tiroides/patología , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteoglicanos/metabolismoRESUMEN
BACKGROUND: Targeting ACC1 (acetyl coenzyme A carboxylase 1) to restore the balance between T-helper 17 (Th17) cells and regulatory T cells (Tregs) through metabolic reprogramming has emerged as a promising strategy for reducing neuroinflammation following stroke. We examined the roles of potential miRNAs in regulating ACC1 expression in Tregs and treating ischemic stroke. METHODS: The expression of miR-24-3p in CD4+T cells of mice was confirmed. Then the protective effects of Ago-24-3p in a mouse model of prolonged occlusion of the distal middle cerebral artery (dMCAO) were examined. We analyzed the infiltration of Tregs and CD3+T cells into the brain and evaluated the improvement of neurological deficits induced by Ago-24-3p using the Modified Garcia Score and foot fault testing. RESULTS: Our investigation revealed that miR-24-3p specifically targets ACC1. Elevated levels of miR-24-3p have been demonstrated to increase the population of Tregs and enhance their proliferation and suppressive capabilities. Conversely, targeted reduction of ACC1 in CD4+T cells has been shown to counteract the improved functionality of Tregs induced by miR-24-3p. In a murine model of dMCAO, administration of Ago-24-3p resulted in a substantial reduction in the size of the infarct within the ischemic brain area. This effect was accompanied by an upregulation of Tregs and a downregulation of CD3+T cells in the ischemic brain region. In ACC1 conditional knockout mice, the ability of Ago-24-3p to enhance infiltrating Treg cells and diminish CD3+T cells in the ischemic brain area has been negated. Furthermore, its capacity to reduce infarct volume has been reversed. Furthermore, we demonstrated that Ago-24-3p sustained improvement in post-stroke neurological deficits for up to 4 weeks after the MCAO procedure. CONCLUSIONS: MiR-24-3p shows promise in the potential to reduce ACC1 expression, enhance the immunosuppressive activity of Tregs, and alleviate injuries caused by ischemic stroke. These discoveries imply that miR-24-3p could be a valuable therapeutic option for treating ischemic stroke.
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Acetil-CoA Carboxilasa , Isquemia Encefálica , MicroARNs , Linfocitos T Reguladores , Células Th17 , Animales , Ratones , Acetil-CoA Carboxilasa/genética , Isquemia Encefálica/inmunología , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismoRESUMEN
Brain disorders are a series of conditions with damage or loss of neurons, such as Parkinson's disease (PD), Alzheimer's disease (AD), or drug dependence. These individuals have gradual deterioration of cognitive, motor, and other central nervous system functions affected. This degenerative trajectory is intricately associated with dysregulations in neurotransmitter systems. Positron Emission Tomography (PET) imaging, employing radiopharmaceuticals and molecular imaging techniques, emerges as a crucial tool for detecting brain biomarkers. It offers invaluable insights for early diagnosis and distinguishing brain disorders. This article comprehensively reviews the application and progress of conventional and novel PET imaging agents in diagnosing brain disorders. Furthermore, it conducts a thorough analysis on merits and limitations. The article also provides a forward-looking perspective in the future development directions of PET imaging agents for diagnosing brain disorders and proposes potential innovative strategies. It aims to furnish clinicians and researchers with an all-encompassing overview of the latest advancements and forthcoming trends in the utilization of PET imaging for diagnosing brain disorders.
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Encéfalo , Enfermedades del Sistema Nervioso , Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Radiofármacos , AnimalesRESUMEN
Aims: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. Materials and methods: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix. Results: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL. Conclusions: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Adulto , Humanos , Hipoglucemiantes/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Hemoglobina Glucada , Péptido C , Glucemia , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/uso terapéutico , Péptido 1 Similar al Glucagón , Insulina/uso terapéuticoRESUMEN
Adipose tissues (AT) are an important endocrine organ that secretes various functional adipokines, peptides, non-coding RNAs, and acts on AT themselves or other distant tissues or organs through autocrine, paracrine, or endocrine manners. An accumulating body of evidence has suggested that many adipokines play an important role in liver metabolism. Besides the traditional adipokines such as adiponectin and leptin, many novel adipokines have recently been identified to have regulatory effects on the liver. Additionally, AT can produce extracellular vesicles (EVs) that act on peripheral tissues. However, under pathological conditions, such as obesity and diabetes, dysregulation of adipokines is associated with functional changes in AT, which may cause liver diseases. In this review, we focus on the newly discovered adipokines and EVs secreted by AT and highlight their actions on the liver under the context of obesity, nonalcoholic fatty liver diseases (NAFLD), and some other liver diseases. Clarifying the action of adipokines and adipose tissue-derived EVs on the liver would help to identify novel therapeutic targets or biomarkers for metabolic diseases.
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Adipoquinas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Adipoquinas/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Adiponectina , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
It is known that hydroxyapatite-type calcium phosphate cement (CPC) shows appreciable self-curing properties, but the phase transformation products often lead to slow biodegradation and disappointing osteogenic responses. Herein, we developed an innovative strategy to endow invisible micropore networks, which could tune the microstructures and biodegradation of α-tricalcium phosphate (α-TCP)-based CPC by gypsum fibers, and the osteogenic capability of the composite cements could be enhanced in vivo. The gypsum fibers were prepared via extruding the gypsum powder/carboxylated chitosan (CC) slurry through a 22G nozzle (410 µm in diameter) and collecting with a calcium salt solution. Then, the CPCs were prepared by mixing the α-TCP powder with gypsum fibers (0-24 wt %) and an aqueous solution to form self-curing cements. The physicochemical characterizations showed that injectability was decreased with an increase in the fiber contents. The µCT reconstruction demonstrated that the gypsum fiber could be distributed in the CPC substrate and produce long-range micropore architectures. In particular, incorporation of gypsum fibers would tune the ion release, produce tunnel-like pore networks in vitro, and promote new bone tissue regeneration in rabbit femoral bone defects in vivo. Appropriate gypsum fibers (16 and 24 wt %) could enhance bone defect repair and cement biodegradation. These results demonstrate that the highly biodegradable cement fibers could mediate the microstructures of conventional CPC biomaterials, and such a bicomponent composite strategy may be beneficial for expanding clinical CPC-based applications.
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Sulfato de Calcio , Hidroxiapatitas , Osteogénesis , Animales , Conejos , Sulfato de Calcio/farmacología , Polvos , Fosfatos de Calcio/farmacología , Fosfatos de Calcio/química , Cementos para Huesos/farmacología , Cementos para Huesos/químicaRESUMEN
Background: Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection. Methods: We conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results. Results: An indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96-1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01-0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00-0.78; P<0.001) had a lower incidence of overall adverse events (AEs). Conclusion: Pembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern. Systematic review registration: https://inplasy.com/, identifier INPLASY202410078.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Metaanálisis en Red , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Nivolumab/administración & dosificación , Anilidas/efectos adversos , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Resultado del Tratamiento , Supervivencia sin ProgresiónRESUMEN
Background: The discovery of phospholipase A2 receptor (PLA2R) and its antibody (aPLA2Rab) has paved the way for diagnosing PLA2R-associated membranous nephropathy (PLA2R-MN) with a high specificity of 98%. However, the sensitivity was only 40% to 83.9%, and there is ongoing discussion around determining the optimal threshold for diagnosis. Recent advancements in the use of exosomes, a novel form of "liquid biopsy," have shown great promise in identifying markers for various medical conditions. Methods: Protein mass spectrometry and western blot were applied to verify the existence of PLA2R antigen in the urine exosome. We then evaluated the efficacy of urinary exosomal PLA2R antigen alone or combined with serum aPLA2Rab level to diagnose PLA2R-MN. Results: The urinary exosomes contained a high abundance of PLA2R antigen as evidenced by protein mass spectrometry and western blot in 85 PLA2R-MN patients vs the disease controls (14 secondary MN patients, 22 non-MN patients and 4 PLA2R-negative MN patients) and 20 healthy controls. Of note, urinary exosomal PLA2R antigen abundance also had a good consistency with the PLA2R antigen level in the renal specimens of PLA2R-MN patients. The sensitivity of urinary exosomal PLA2R for diagnosing PLA2R-MN reached 95.4%, whereas the specificity was 63.3%. Combining detection of the urinary exosomal PLA2R and serum aPLA2Rab could develop a more sensitive diagnostic method for PLA2R-MN, especially for patients with serum aPLA2Rab ranging from 2 to 20 RU/mL. Conclusions: Measurement of urinary exosomal PLA2R could be a sensitive method for the diagnosis of PLA2R-MN.
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Herein, ZIF-8 inorganic particles with different sized reinforced poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) solid composite polymer electrolytes (PVDF-HFP/10%ZIF-8) were prepared via a facile blade-coating approach, and free-standing quasi solid-state composite electrolytes (PVDF-HFP/10%ZIF-8(0.6)/Plasticizer, abbreviated as PH/10%ZIF-8(0.6)/P), were further obtained through the introduction of plasticizer. Optimized PH/10%ZIF-8(0.6)/P exhibited a high ionic conductivity of 2.8 × 10-4 S cm-1 at 30 °C, and superior Li+ transfer number of 0.89 with an ultrathin thickness (26 µm). Therefore, PH/10%ZIF-8(0.6)/P could effectively inhibit the growth of lithium dendrites, and the assembled Li/LiFePO4 cell delivered good cycling stability with a capacity retention rate of 89.1% after 100 cycles at 0.5 C.
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Introduction: Brown adipose tissue (BAT) is mainly responsible for mammalian non-shivering thermogenesis and promotes energy expenditure. Meanwhile, similar to white adipose tissue (WAT), BAT also secretes a variety of adipokines to regulate metabolism through paracrine, autocrine, or endocrine ways. The chemokine C-X-C motif chemokine ligand-13 (CXCL13), a canonical B cell chemokine, functions in inflammation and tumor-related diseases. However, the role of CXCL13 in the adipose tissues is unclear. Methods: The expression of CXCL13 in BAT and subcutaneous white adipose tissue (SWAT) of mice under cold stimulation were detected. Local injection of CXCL13 into BAT of normal-diet and high-fat-diet induced obese mice was used to detect thermogenesis and determine cold tolerance. The brown adipocytes were treated with CXCL13 alone or in the presence of macrophages to determine the effects of CXCL13 on thermogenic and inflammation related genes expression in vitro. Results: In this study, we discovered that the expression of CXCL13 in the stromal cells of brown adipose tissue significantly elevated under cold stimulation. Overexpression of CXCL13 in the BAT via local injection could increase energy expenditure and promote thermogenesis in obese mice. Mechanically, CXCL13 could promote thermogenesis via recruiting M2 macrophages in the BAT and, in the meantime, inhibiting pro-inflammatory factor TNFα level. Discussion: This study revealed the novel role of adipose chemokine CXCL13 in the regulation of BAT activity and thermogenesis.
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Tejido Adiposo Pardo , Quimiocina CXCL13 , Animales , Ratones , Tejido Adiposo Pardo/metabolismo , Quimiocina CXCL13/metabolismo , Macrófagos/metabolismo , Mamíferos , Ratones Obesos , Termogénesis/genéticaRESUMEN
BACKGROUND: Ilizarov method has become one of primary methods for treating bone defects. Currently, there is growing trend in the application of modified Ilizarov methods (e.g., applying unilateral external fixators or with flap tissue) and its combined methods (e.g., Ilizarov method with antibiotic spacer or internal fixation) to manage bone defects. However, there is a lack of studies with systematical evaluation of the clinical effects of these evolving methods. This study aimed to conduct a systematic review and meta-analysis for overall evaluating the clinical effects on long bone defects of lower extremity in Ilizarov methods and its combined methods. METHODS: Studies were identified in three electronic databases (Pubmed, Embase and Cochrane Library) from the earliest indexing year through November 01, 2022, and relevant data were extracted subsequently. The total number of participants, number of participants with bone unions, bone result or functional result, and related complications including pin infection, pin loosening, pain, refracture, limb discrepancy, malalignment, joint stiffness, recurrent infection, and amputation were extracted in this study. Then, union rate (defined as the proportion of patients who achieved bone unions) and specific complication incidence rate (defined as the proportion of patients who experienced specific complication) were pooled estimated respectively. Relative risk (RR) was used for comparing the clinical effects among various Ilizarov technique. RESULTS: Sixty-eight case series studies, 29 comparative studies, and 3 randomized clinical trials were finally included. The union rate of Ilizarov methods was 99.29% (95% CI: 98.67% ~ 99.86%) in tibial defects and 98.81% (95% CI: 98.81% ~ 100.00%) in femoral defects. The union rate of Ilizarov method with antibiotic spacer and intramedullary nail in tibial defects was 99.58% (95% CI: 98.05% ~ 100.00%) and 95.02% (95% CI: 87.28% ~ 100.00%), respectively. Compared to the Ilizarov methods, the union rate of the Ilizarov method with antibiotic spacer in tibial defects increased slightly (RR = 1.02, 95% CI: 1.01 ~ 1.04). Meanwhile, compared to Ilizarov methods, we found lower excellent rate in bone result in Ilizarov method with antibiotic spacer, with the moderate to high heterogeneity. Compared to the Ilizarov method, lower rate of pin infection, higher rate of recurrent infection and amputation were observed in Ilizarov method with intramedullary nail, however, the findings about the comparison of pin infection and recurrent infection between the two groups were presented with high degree of statistical heterogeneity. CONCLUSION: Our study confirmed the reliable treatment of Ilizarov methods and its combined technique on long bone defects, and founded there were significant differences on some complications rate between Ilizarov methods and its combined technique. However, the findings need to be confirmed by further studies.
Asunto(s)
Técnica de Ilizarov , Fracturas de la Tibia , Humanos , Reinfección , Resultado del Tratamiento , Tibia/cirugía , Fijadores Externos , Extremidad Inferior/cirugía , Antibacterianos , Estudios Retrospectivos , Fracturas de la Tibia/cirugíaRESUMEN
Background: Studies using novel antiandrogens (NAA) in patients with metastatic castration-resistant prostate cancer (mCRPC) have shown overall survival benefit. As patients develop resistance to NAA therapy, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib in combination with NAA may become a promising therapy. However the overall benefit of olaparib monotherapy or combination therapy still needs to be evaluated. Therefore, we performed a network meta-analysis to assess the efficacy and toxicity between olaparib, olaparib combined with abiraterone and NAA. Methods: We searched PubMed, EMBASE, the Cochrane Library and American Society of Clinical Oncology (ASCO) University Meeting abstracts for randomized controlled trials reporting olaparib and NAA from 2010 up to March, 2023. Network meta-analysis using Stata 16.0 and R 4.4.2, hazard ratios (HR) with 95% confidence intervals (CI) were used to assess the results. Results: Four trials reported olaparib, olaparib plus abiraterone and apalutamide plus abiraterone. radiographic progression-free survival (rPFS) was significantly lower in patients on apalutamide plus abiraterone compared to olaparib (HR, 1.43; 95% CI, 1.06-1.93). rPFS was similar for olaparib plus abiraterone and olaparib (HR, 1.35; 95% CI, 0.99-1.84); likewise, olaparib plus abiraterone and apalutamide plus abiraterone were similar (HR, 1.06; 95% CI, 0.83-1.35). In addition, there was no significant difference between the three interventions for OS. But olaparib has the highest probability of being a preferred treatment for improving rPFS and OS. Conclusion: rPFS was in favor of olaparib compared with apalutamide plus abiraterone. But there were no difference between olaparib plus abiraterone and either olaparib or apalutamide plus abiraterone. Apalutamide plus abiraterone might be the most preferred intervention in cases where AEs are involved. Systematic review registration: https://inplasy.com, identifier INPLASY2023100072.