Structural and functional properties of Maillard-reacted casein phosphopeptides with different carbohydrates.

This study used glucose, fructose, maltose and dextran to explore the effects of different carbohydrates on the Maillard reaction of casein phosphopeptides (CPP). The color parameter results showed that heating time from 1 to 5 h led to brown color, which was consistent with the observed increased in browning intensity. Fourier transform infrared spectroscopy results verified that four carbohydrates reacted with CPP to produce Maillard conjugates. Fluorescence spectroscopy showed that the Maillard reaction changed the tertiary structure of CPP by decreasing the intrinsic fluorescence intensity and surface hydrophobicity compared with the CPP-carbohydrate mixture. At the same time, the Maillard reaction effectively improved the emulsifying properties, reducing power and DPPH radical scavenging activity of CPP. Furthermore, this study also found that glucose and fructose improved CPP more than maltose and dextran. Therefore, monosaccharides have good potential in modifying CPP via the Maillard reaction.

Active pullulan-based coatings incorporated with Auricularia auricular extracts for preserving potato fresh-cuts.

In the present study, Auricularia auricular polysaccharides (AAP) and Auricularia auricular proteins (AAPR) obtained from the waste products of Auricularia auricular were incorporated into pullulan (PUL) to obtain active packaging films/coatings. Results showed that incorporating AAP/AAPR into PUL-based films decreased their transparency, but increased the compactness, thermal stability, antioxidant, and antimicrobial properties. Adding 2% PUL films with 10%:10% of AAP/AAPR exhibiting good mechanical properties were applied to fresh-cut potatoes to avoid spoilage during eight days of storage, with significantly decreased in browning index, weight loss, microbial growth prevention and the total soluble solids was maintained. These results substantiated that pullulan containing AAP/AAPR as an active film/coating with antioxidant and antimicrobial properties has significant potential for maintaining safety and quality of fresh-cut potatoes and extending their shelf life.

Latamoxef dosing regimen adjustments and pharmaceutical care in pediatrics.

Latamoxef is a semi-synthetic, broad-spectrum oxacephem antibiotic used primarily to treat infectious diseases, but the adverse drug reactions, such as the risk of fatal bleeding, once caused physicians to use it less frequently. However, with the rise of antibiotic-resistant bacterial strains, latamoxef is being used again to treat infectious diseases, especially in pediatrics. The pharmacokinetic parameters of latamoxef are highly variable, given the changes in body composition, organ maturation, and development that occurs in pediatrics. Therefore, an appropriate dosing regimen is essential. Latamoxef dosing optimization in pediatrics should adequately account for current body weight, postnatal age, postmenstrual age, and different minimum inhibitory concentration (MIC) values. In addition, attention should also be paid to some of the adverse reactions associated with latamoxef, such as coagulation disorders and bleeding risks, disulfiram-like reactions, as well as hypersensitivity and anaphylactic shock. This review summarizes the dosing regimens and some key points of pharmaceutical care for latamoxef in pediatrics in order to provide a better reference for its application in clinical practice.

A pharmacovigilance study of association between proton-pump inhibitors and rhabdomyolysis event based on FAERS database.

BACKGROUND AND AIM: The association between proton-pump inhibitors (PPIs) and rhabdomyolysis were unclear. The aim of this study was to explore and systematically analyze the potential link between five PPIs and the rhabdomyolysis events using the FDA Adverse Event Reporting System (FAERS) database. METHODS: Suspected rhabdomyolysis events associated with PPIs were identified by data mining with the reporting odds ratio (ROR), proportional reporting ratio (PRR), the information component (IC), and Empirical Bayes Geometric Mean (EBGM). Demographic information, drug administration, and outcomes of PPI-induced rhabdomyolysis events were also analyzed. RESULTS: There were 3311 reports associated with PPI-induced rhabdomyolysis that were identified. After removing duplicates, 1899 cases were determined to contain complete patient demographic data. The average age was 65 ± 18 year and 57% were male. Omeprazole and pantoprazole had the same largest percentage of reports. Lansoprazole had the highest ROR index of 12.67, followed by esomeprazole (11.18), omeprazole (10.27), rabeprazole (10.06), and pantoprazole (9.24). PRR, IC, and EBGM showed similar patterns. This suggested that lansoprazole exhibited the strongest correlation with rhabdomyolysis. In rhabdomyolysis events, PPIs were mainly "concomitant" (>60%), and only a few cases were "primary suspects" (<15%). Rabeprazole showed the lowest death rate while lansoprazole showed the highest. CONCLUSIONS: The study suggested that significant rhabdomyolysis signals were associated with PPIs. Further research should be performed in drug safety evaluation for a more comprehensive association.

Vardenafil alleviates cigarette smoke-induced chronic obstructive pulmonary disease by activating autophagy via the AMPK/mTOR signalling pathway: an in vitro and in vivo study.

Chronic obstructive pulmonary disease (COPD) has always attracted global attention with its high prevalence, incidence rate, and mortality. Exposure to cigarette smoke is one of main causes of COPD. Therefore, it is still necessary to study its pathogenesis and find new therapeutic strategies for early COPD prevention and treatment. Vardenafil, a type 5 phosphodiesterase (PDE5) inhibitor, is known to have an efficient therapy in some cardiovascular, pulmonary, and vascular diseases, which is an important mechanism for COPD. However, it still loss relevant research on whether vardenafil is effective in COPD and its mechanism. In this study, the cigarette smoke inhalation was performed to establish cigarette smoke-induced COPD model using C57BL/6 mice and 16HBE cells were treated with cigarette smoke extract (CSE). Mice were treated with vardenafil for 30 d. Then condition of lung injury was evaluated using histological analysis. The content of cytokines and the number of inflammatory cells in lung tissues or bronchoalveolar lavage fluid were measured. Additionally, western blot analysis was employed to evaluate the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)-mediated autophagy in vitro. The results showed that vardenafil abolished CSE's effect by activating autophagy via the AMPK/mTOR signalling pathway in vitro. Vardenafil attenuated cigarette smoke-induced lung injury and inflammation response by activating autophagy via the AMPK/mTOR signalling pathway in vivo. These results provide valuable insights into the molecular mechanisms underlying vardenafil's beneficial effects in cigarette smoke-induced COPD treatment. In conclusion, vardenafil alleviates cigarette smoke-induced experimental COPD by activating autophagy via the AMPK/mTOR signalling pathway.

Identifying Sex-Specific Serum Patterns of Alzheimer's Mice through Deep TMT Profiling and a Concentration-Dependent Concatenation Strategy.

Alzheimer's disease (AD) is the most prevalent form of dementia, disproportionately affecting women in disease prevalence and progression. Comprehensive analysis of the serum proteome in a common AD mouse model offers potential in identifying possible AD pathology- and gender-associated biomarkers. Here, we introduce a multiplexed, nondepleted mouse serum proteome profiling via tandem mass-tag (TMTpro) labeling. The labeled sample was separated into 475 fractions using basic reversed-phase liquid chromatography (RPLC), which were categorized into low-, medium-, and high-concentration fractions for concatenation. This concentration-dependent concatenation strategy resulted in 128 fractions for acidic RPLC-tandem mass spectrometry (MS/MS) analysis, collecting ∼5 million MS/MS scans and identifying 3972 unique proteins (3413 genes) that cover a dynamic range spanning at least 6 orders of magnitude. The differential expression analysis between wild type and the commonly used AD model (5xFAD) mice exhibited minimal significant protein alterations. However, we detected 60 statistically significant (FDR < 0.05), sex-specific proteins, including complement components, serpins, carboxylesterases, major urinary proteins, cysteine-rich secretory protein 1, pregnancy-associated murine protein 1, prolactin, amyloid P component, epidermal growth factor receptor, fibrinogen-like protein 1, and hepcidin. The results suggest that our platform possesses the sensitivity and reproducibility required to detect sex-specific differentially expressed proteins in mouse serum samples.

Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis.

Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.

The state and consideration for skin test of ß-lactam antibiotics in pediatrics.

ß-lactam antibiotics are the most frequently used drugs and the most common drugs that cause allergic reactions in pediatrics. The occurrence of some allergic reactions can be predicted by skin testing, especially severe adverse reactions such as anaphylactic shock. Thus, penicillin and cephalosporin skin tests are widely used to predict allergic reactions before medication in pediatrics. However, false-positive results from skin tests were more often encountered in pediatrics than in adults. In fact, many children labeled as allergic to ß-lactam are not allergic to the antibiotic, leading to the use of alternative antibiotics, which are less effective and more toxic, and the increase of antibiotic resistance. There has been controversy over whether ß-lactam antibiotics should be tested for skin allergies before application in children. Based on the great controversy in the implementation of ß-lactam antibiotic skin tests, especially the controversial cephalosporin skin tests in pediatrics, the mechanism and reasons of anaphylaxis to ß-lactam antibiotics, the significance of ß-lactam antibiotic skin tests, the current state of ß-lactam antibiotic skin tests at home and abroad, and the problems of domestic and international skin tests were analyzed to determine a unified standard of ß-lactam antibiotic skin tests in pediatrics to prevent and decrease adverse drug reactions, avoid waste of drugs, and a large amount of manpower and material resource consumption.

Hollow porphyrin-based porous organic polymer with dual enzyme-like activities for ultra-fast colorimetric detection of Cr (VI) in wastewater.

A hollow porphyrin-based porous organic polymer (H-Fe-POP) was prepared for rapid and sensitive colorimetric determination of Cr(VI), which exhibited excellent dual enzyme-like activities, including oxidase-like and peroxidase-like activities. Due to the specific binding of 8-hydroxyquinoline (8-HQ) to Cr(VI), 3,3',5,5'-tetramethylbenzidine (TMB) was liberated, and TMB was oxidized to blue ox-TMB catalyzed by H-Fe-POP. Based on the excellent oxidase-like activity of H-Fe-POP, an ultra-fast colorimetric platform for the detection of Cr(VI) was constructed, allowing the quantification of Cr(VI) in the range 2-130 µM within 30 s with a detection limit of 0.23 µM. Importantly, the sensor can accurately determine Cr(VI) in industrial wastewater, indicating its high potential for environmental monitoring.

Differences in Hepatocellular Iron Metabolism Underlie Sexual Dimorphism in Hepatocyte Ferroptosis.

Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe 2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe 2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.

Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors.

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. A population pharmacokinetic model was established using nonlinear mixed-effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1-compartment model with first-order absorption and first-order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.

Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse.

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.

Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse.

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 ( RRM2 ) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B . Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.

Spatiotemporal regulation of cholangiocarcinoma growth and dissemination by peritumoral myofibroblasts in a Vcam1-dependent manner.

Intrahepatic cholangiocarcinoma (iCCA) is characterized by its highly desmoplastic stroma. Myofibroblasts (MFs) are present both within the tumor mass (intratumoral MFs, iMFs) and at the tumor border (peritumoral MFs, pMFs). Using a spheroid-based coculture system, we show that the initial iCCA-pMF contact is growth suppressive to the tumor cells. However, prolonged iCCA-pMF interaction elicits significant tumor cell invasion and dissemination. We find that vascular cell adhesion molecule-1 (Vcam1) level is elevated in tumor cells in contact with pMFs but low in disseminated tumor cells both in vitro and in vivo. A gene regulatory network analysis of mouse and patient iCCA tumors and Vcam1 knockout (Vcam1KO) demonstrate a heavy involvement of Vcam1 in epithelial-to-mesenchymal transition. While Vcam1KO has only a limited impact on tumor cell growth in their monoculture, Vcam1KO spheroids exhibit instant dissemination and a severe growth defect when cocultured with pMFs. When transplanted into the liver, Vcam1KO iCCA cells show a similar increase in dissemination but a significant defect in establishing primary and metastatic tumors. Incomplete blocking of Vcam1 in vivo reduces the size but increase the number of metastatic lesions. Overall, our study shows a spatiotemporal regulation of iCCA growth and dissemination by pMFs in a Vcam1-dependent manner.

A hepatoprotective role of peritumoral non-parenchymal cells in early liver tumorigenesis.

Various 3D models of hepatocytes (HCs) have been established to assess liver functions in vitro. The contribution of the hepatic non-parenchymal cells (NPCs), however, is largely neglected in these models. Here, we report a comparative study of hepatic spheroids generated from freshly isolated mouse whole liver cells (WLCs) and HCs (referred to as SphWLC and SphHC, respectively). We found that HC differentiation was preserved better in SphWLC than in SphHC, and, when co-cultured with liver tumor spheroids (SphT), SphWLC showed more potent suppression of SphT growth compared to SphHC. Histological characterization revealed marked activation and accumulation of hepatic stellate cells (HSCs) at the SphWLC:SphT interface. We found that mixing HSCs in both 3D and 2D HC:tumor co-cultures provided potent protection to HCs against tumor-induced cell death. Activation of HSCs at the tumor border was similarly found in liver tumors from both mice and patients. Overall, our study suggests a hepatoprotective role of peritumoral HSCs in liver tumorigenesis and the potential application of SphWLC as a useful 3D model for dissecting the liver's response to tumorigenesis in vitro.

[Response of Topsoil Fungal Community Structure to Soil Improvement Measures in Degraded Forest of Red Soil Region].

Soil fungal community structure and diversity are highly sensitive to variations in the external environment, as well as soil improvement measures. In order to clarify the effects of soil improvement measures on topsoil fertility or quality, a field experiment was conducted in eroded forest of a red soil region. Organic fertilizer, biochar, and lime+microbial fertilizer were added to the topsoil, respectively. After four years, the chemistry properties and nutrients in the topsoil were measured, and the diversity and composition of fungi were analyzed. The results showed that the additions of organic fertilizer, biochar, and lime+microbial fertilizer reduced fungal richness in topsoil, compared to that with no fertilizer addition (CK). Among them, lime+microbial fertilizer had the most negative effect on fungal richness. The three soil improvement measures also affected the diversity of topsoil fungi, but the impacts were not significant. The dominant fungal phyla in the topsoil were Ascomycota (31.29%-46.55%) and Basidiomycota (30.07%-70.71%), and the dominant fungal genera were Amphinema and Archaeorhizomyces. The effects of soil improvement measures on fungal community structure in the topsoil were different; organic fertilizer increased the relative abundance of Ascomycetes and Archaeopteroides, and biochar enhanced the relative abundance of Basidiomycetes and Archaeopteroides, whereas lime+microbial fertilizer improved the relative abundance of Basidiomycetes and Archaeopteroides. Fungal diversity and community structure in the topsoil was affected by edaphic factors, and fungal richness was regulated by pH value, whereas fungal community structure was influenced by pH, total nitrogen, and organic carbon. This study provides scientific guidance for soil improvement and ecological restoration below the canopy in eroded forests of red soil regions.

Amelioration of Chilling Injury by Fucoidan in Cold-Stored Cucumber via Membrane Lipid Metabolism Regulation.

Cucumber fruit is very sensitive to chilling injury, which rapidly depreciates their commodity value. Herein, the effect of fucoidan treatment on cucumber under cold stress were investigated. Fucoidan treatment of cold-stored cucumber alleviated the occurrence of chilling injury, delayed weight loss, lowered electrolyte leakage and respiration rate, and retarded malondialdehyde accumulation. Different from the control fruit, fucoidan treated fruit showed a high level of fatty acid unsaturated content, fatty acid unsaturation, and unsaturation index and increased ω-FDAS activity, along with upregulated expression levels of CsSAD and CsFAD genes. Fucoidan reduced the phosphatidic acid content and membrane lipid peroxidation, lowered the phospholipase D (PLD) and lipoxygenase (LOX) activity, and downregulated the expression levels of CsPLD and CsLOX genes. Collectively, fucoidan treatment maintained the integrity of cell membrane in cold-stress cucumbers. The results provide a new prospect for the development of fucoidan as a preservative agent in the low-temperature postharvest storage of cucumbers.

Long-term assessment on performance and seasonal optimal operation of a full-scale integrated multiple constructed wetland-pond system.

Constructed wetlands as natural process-based water treatment technologies are popular globally. However, lack of detailed long-term assessment on the impact of seasonal variations on their performance with focus on optimal seasonal adjustments of controllable operating parameters significantly limits their efficient and sustainable long-term operation. To address this, a full-scale integrated multiple surface flow constructed wetlands-pond system situated between slightly polluted river water and outflow-receiving waterworks in a subtropical monsoon climate area of middle-eastern China was seasonally assessed over a period of six years. During this period, the removal rate (R) and mass removal rate (MRR) of total nitrogen (TN), total phosphorus (TP) and chemical oxygen demand (COD) possessed strong seasonality (p < 0.05). The highest R (%) and MRR (mg/m2/d) were in summer for TN (51.53 %, 114.35), COD (16.30 %, 143.85) and TP (62.39 %, 23.89) and least in spring for TN (23.88 %, 39.36) and COD. Whereas for TP, the least R was in autumn (37.82 %) and least MRR was in winter (9.35). Applying a first-order kinetics model coupled with Spearman's rank correlation analysis, purification efficiency exhibited significant dependence on temperature as nutrient reaction rates constant, k generally increased with temperature and was highest in summer. Meanwhile, the R of TN, TP and COD were positively correlated with influent concentration whiles MRR of TP was negatively correlated with hydraulic retention time but positively correlated with hydraulic loading rate (HLR) (p < 0.05). Also, MRR of COD and TN were positively correlated with mass loading rates (MLR) in summer and autumn. Through linear optimization, the best operating parameters according to the compliance rate were determined and a set of guidelines were proposed to determine the optimal operational change of hydrological index in each season (Spring, 0.1-0.12 m/d; Summer, 0.14-0.16 m/d; Autumn, 0.15-0.17 m/d; Winter, 0.1-0.11 m/d) for efficient and sustainable long-term operation.

Trousseau's syndrome in a non-small cell lung cancer patient aggravated by pembrolizumab.

INTRODUCTION: We present a case of Trousseau's syndrome in a non-small cell lung cancer patient recurrently aggravated by pembrolizumab. The adverse events related to immune checkpoint inhibitors (ICIs) on thrombogenesis remain unclear. CASE REPORT: A 48-year-old woman was diagnosed with right lung adenocarcinoma (cT1bN3M1a, IVA) and with programmed cell death-1 positive. Brain magnetic resonance imaging (MRI) showed multiple asymptomatic bilateral cerebral infarctions as Trousseau's syndrome. After the patient was administered pembrolizumab, bilateral cerebral infarctions were aggravated. MANAGEMENT AND OUTCOME: Although the patient was given prophylactic anticoagulant therapy respectively before two doses of pembrolizumab, Trousseau's syndrome still aggravated recurrently. DISCUSSION: Trousseau's syndrome is rarely reported following the administration of ICIs. It is possible that pembrolizumab may trigger disorders of the coagulation-fibrinolysis system in cancer patients.

Population Pharmacokinetics of Tacrolimus in Pediatric Patients With Umbilical Cord Blood Transplant.

Tacrolimus was frequently used in pediatric patients with umbilical cord blood transplant for the prevention of graft-versus-host disease. The aim of the present study was to evaluate the population pharmacokinetics of tacrolimus among pediatric patients with umbilical cord blood transplant and find potential influenced factors. A total of 275 concentrations from 13 pediatric patients were used to build a polulation pharmacokinetic model using a nonlinear mixed-effects modeling approach. The impact of demographic features, biological characteristics, and concomitant medications, including sex, age, body weight, postoperative day, white blood cell count, red blood cell count, hemoglobin, platelets, hematocrit, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, total bilirubin, albumin, and total protein were investigated. The pharmacokinetics of tacrolimus were best described by a 1-compartment model with first- and zero-order mixed absorption and first-order elimination. The clearance and volume of distribution of tacrolimus were 1.93 L/h and 75.1 L, respectively. A covariate analysis identified that postoperative day and co-administration with trimethoprim-sulfamethoxazole were significant covariates influencing clearance of tacrolimus. Frequent blood monitoring and dose adjustment might be needed with the prolongation of postoperative day and coadministration with trimethoprim-sulfamethoxazole.