Population pharmacokinetic analyses of methotrexate in pediatric patients: a systematic review.

BACKGROUND AND OBJECTIVES: Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients. METHODS: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed. RESULTS: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models. CONCLUSION: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.

Effectiveness of prophylactic antibacterial drugs for patients with liver cirrhosis and upper gastrointestinal bleeding: a systematic review and meta-analysis.

Background: Prophylactic antibacterial drugs are used for patients with liver cirrhosis and upper gastrointestinal bleeding, and independent studies have concluded that they can decrease the rate of infection, mortality, and rebleeding in these diseases. However, no comprehensive assessment of this effect has been reported in recent years and available data pertaining to the prognostic implications of diverse categories of antibiotic prophylaxis in individuals afflicted with cirrhosis are notably limited. The objective of this article is to assess the clinical effectiveness of prophylactic antibacterial drugs for patients with liver cirrhosis and upper gastrointestinal bleeding. Methods: Relevant randomized controlled studies and cohort studies which examined the value of prophylactic antibacterial drugs for patients with liver cirrhosis and upper gastrointestinal bleeding were retrieved via Cochrane Library, EMBASE, MedLine, and Web of Science. The search period was from database inception until 30 April 2023. Summing up the relevant data, the dichotomous variable was statistically analysed using the relative risk (RR) value and its 95% confidence interval (CI) and the continuous variable using the mean difference (MD) value and its 95% CI. All analyses were performed using Revman 5.4 software. The study has been registered on the PROSPERO website under registration number CRD42022343352. Results: Twenty-six studies (18 RCTs and 8 cohort studies, including 13,670 participants) were included to evaluate the effect of antibacterial prophylaxis versus no antibacterial prophylaxis or placebo. Prophylactic antibiotics reduced mortality rates (RR 0.66, 95% CI 0.51-0.83), infection rates (RR 0.41, 95% CI 0.35-0.49), rebleeding rates (RR 0.42, 95% CI 0.31-0.56), and length of hospital stay (MD -5.29, 95% CI -7.53, -3.04). Subgroup analysis revealed that the prophylactic administration of quinolone antimicrobials demonstrated the most favorable efficacy, followed by cephalosporins. Both interventions were effective in averting infections frequently observed in patients with liver cirrhosis and upper gastrointestinal bleeding. Conclusion: Based on our investigation, the prophylactic antibacterial drugs confers noteworthy advantages in patients afflicted by liver cirrhosis with upper gastrointestinal bleeding. It has been associated with reductions in mortality, infection incidence, rebleeding occurrences, and the duration of hospitalization. Among prophylactic antibacterial options, quinolones emerged as the foremost choice, with cephalosporins ranking closely thereafter. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022343352, identifier CRD42022343352.

An overview of the regulatory role of annexin A1 in the tumor microenvironment and its prospective clinical application (Review).

Although annexin A1 (ANXA1), a 37 kDa phospholipid­binding anti­inflammatory protein expressed in various tissues and cell types, has been investigated extensively for its regulatory role in cancer biology, studies have mainly focused on its intracellular role. However, cancer cells and stromal cells expressing ANXA1 have the ability to transmit signals within the tumor microenvironment (TME) through autocrine, juxtacrine, or paracrine signaling. This bidirectional crosstalk between cancer cells and their environment is also crucial for cancer progression, contributing to uncontrolled tumor proliferation, invasion, metastasis and resistance to therapy. The present review explored the important role of ANXA1 in regulating the cell­specific crosstalk between various compartments of the TME and analyzed the guiding significance of the crosstalk effects in promotion or suppressing cancer progression in the development of cancer treatments. The literature shows that ANXA1 is critical for the regulation of the TME, indicating that ANXA1 signaling between cancer cells and the TME is a potential therapeutic target for the development of novel therapeutic approaches for impeding cancer development.

Collision Energy Analysis within the Vertical Shaft Impact Crusher Based on the Computational Fluid Dynamics-Discrete Element Method.

Particles in the vertical shaft impact crusher absorb and dissipate collision energy in the impact breakage. The distribution of the collision energy determines the breakage rate of materials and breakage energy consumption of the entire system. In this paper, the gas-solid coupling method is used to explore the regional distribution of collision energy, collision frequency, and collision energy spectrum of the material particle groups. Hence, a theoretical basis is provided for the efficient and energy-saving design of the crusher. First, a coupling mathematical model of the computational fluid dynamics and discrete element method is established to describe the interaction between material and fluid in the crushing chamber. Moreover, the experiment is carried out using a PL8500 VSI crusher and compared with the simulation results to verify the model's reliability. Finally, the effects of different working conditions on the energy dissipation distribution and energy spectrum are explored. The results show that the collision energy within the crushing chamber can be accurately predicted by using the fluid-solid coupling model. Moreover, increasing the rotational speed can effectively transform low-energy collision events into high-energy collisions and increase the collision frequency with energy dissipation above the threshold energy. Thus, the probability of material breakage is increased. Last, increasing the feed rate minorly affects the material breakage rate, while the specific energy of the entire system is reduced.

Pharmacokinetics, metabolism, excretion and safety of iruplinalkib (WX-0593), a novel ALK inhibitor, in healthy subjects: a phase I human radiolabeled mass balance study.

BACKGROUND: Iruplinalkib is a novel anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive crizotinib-resistant NSCLC. RESEARCH DESIGN AND METHODS: A single oral dose of 120 mg/3.7 MBq [14C]iruplinalkib was administered to healthy subjects. Blood, urine and fecal samples were collected and analyzed for iruplinalkib and its metabolites. The safety of iruplinalkib was also assessed. RESULTS: Iruplinalkib was absorbed quickly and eliminated slowly from plasma, with a Tmax of 1.5 h and t1/2 of 28.6 h. About 88.85% of iruplinalkib was excreted at 312 h, including 20.23% in urine and 68.63% in feces. Seventeen metabolites of iruplinalkib were identified, and M3b (demethylation), M7 (cysteine conjugation), M11 (oxidative dehydrogenation and cysteine conjugation of M3b) and M12 (oxidative dehydrogenation and cysteine conjugation) were considered the prominent metabolites in humans. Iruplinalkib-related compounds were found to be covalently bound to proteins, accounting for 7.70% in plasma and 17.96% in feces, which suggested chemically reactive metabolites were formed. There were no serious adverse events observed in the study. CONCLUSIONS: Iruplinalkib was widely metabolized and excreted mainly through feces in humans. Unchanged iruplinalkib, cysteine conjugates and covalent protein binding products were the main drug-related compounds in circulation. Iruplinalkib was well tolerated at the study dose. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (Identifier: Anonymized).

The reference range of lamotrigine in the treatment of epilepsy in children: a systematic review.

PURPOSE: This study intends to assess the reference range of lamotrigine concentration for treating childhood epilepsy. METHODS: PubMed, Ovid-Embase, The Cochrane Library, CNKI, WanFang data and VIP databases were searched from database inception to January 2022. RCT, cohort study, case-control study, cross-sectional study that estimated the reference range of lamotrigine for children epilepsy treatment were included. The data extracted included basic information, statistical methods, data type, and results of reference range. Descriptive analysis was performed for them. RESULTS: 8 studies were included and estimated the reference range, and all of them were calculated based on efficacy data and/or concentration data. Statistical methods including ROC curve, concentration-effect curve, mean ± standard deviation, 95% confidence interval and percentile interval were utilized. For lamotrigine monotherapy, the lower limits ranged from 2.06 mg/L to 3.99 mg/L, and the upper limits ranged from 8.43 mg/L to 9.08 mg/L, showing basic consistency. However, for lamotrigine concomitant with valproate, the lower limits ranged from 2.00 mg/L to 8.00 mg/L, and the upper limit was 11.50 mg/L, for lamotrigine concomitant with other antiepileptics, the lower limits ranged from 1.00 mg/L to 3.09 mg/L, and the upper limits varied from 5.90 mg/L to 16.24 mg/L, indicating inconsistency. CONCLUSION: Several studies have estimated the reference range of lamotrigine for childhood epilepsy, while controversy exist and no studies have determined the upper limit of the range based on safety data. To establish the optimal reference range, further high-quality studies are necessary that consider both efficacy and safety data.

Research progress in nano-drug delivery systems based on the characteristics of the liver cancer microenvironment.

The liver cancer has microenvironmental features such as low pH, M2 tumor-associated macrophage enrichment, low oxygen, rich blood supply and susceptibility to hematotropic metastasis, high chemokine expression, enzyme overexpression, high redox level, and strong immunosuppression, which not only promotes the progression of the disease, but also seriously affects the clinical effectiveness of traditional therapeutic approaches. However, nanotechnology, due to its unique advantages of size effect and functionalized modifiability, can be utilized to develop various responsive nano-drug delivery system (NDDS) by using these characteristic signals of the liver cancer microenvironment as a source of stimulation, which in turn can realize the intelligent release of the drug under the specific microenvironment, and significantly increase the concentration of the drug at the target site. Therefore, researchers have designed a series of stimuli-responsive NDDS based on the characteristics of the liver cancer microenvironment, such as hypoxia, weak acidity, and abnormal expression of proteases, and they have been widely investigated for improving anti-tumor therapeutic efficacy and reducing the related side effects. This paper provides a review of the current application and progress of NDDS developed based on the response and regulation of the microenvironment in the treatment of liver cancer, compares the effects of the microenvironment and the NDDS, and provides a reference for building more advanced NDDS.

Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury.

Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid metabolism. The changes in lipid metabolism encompass not only the downregulation of fatty acid oxidation (FAO) but also changes in cell membrane lipids and triglycerides metabolism. Regarding glucose metabolism, AKI leads to increased glycolysis, activation of the pentose phosphate pathway (PPP), inhibition of gluconeogenesis, and upregulation of the polyol pathway. Research indicates that inhibiting glycolysis, promoting the PPP, and blocking the polyol pathway exhibit a protective effect on AKI-affected kidneys. Additionally, changes in amino acid metabolism, including branched-chain amino acids, glutamine, arginine, and tryptophan, play an important role in AKI progression. These metabolic changes are closely related to the programmed cell death of renal TECs, involving autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. Notably, abnormal intracellular lipid accumulation can impede autophagic clearance, further exacerbating lipid accumulation and compromising autophagic function, forming a vicious cycle. Recent studies have demonstrated the potential of ameliorating AKI-induced kidney damage through calorie and dietary restriction. Consequently, modifying the energy metabolism of renal TECs and dietary patterns may be an effective strategy for AKI treatment.

Optimizing inhaled corticosteroid use in patients with chronic obstructive pulmonary disease: assessing blood eosinophils, neutrophil-to-lymphocyte ratio, and mortality outcomes in US adults.

Objective: Accurate biomarkers for evaluating mortality rates in patients with chronic obstructive pulmonary disease (COPD) remain scarce. This study aimed to explore the relationships between mortality rates in patients with COPD and blood eosinophil counts, neutrophil counts, and lymphocyte counts, along with the neutrophil-to-lymphocyte ratio (NLR). Additionally, we sought to identify the optimal response values for these biomarkers when utilizing inhaled corticosteroids (ICS). Methods: Utilizing a nationally representative, multistage cross-sectional design and mortality correlation study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 involving US adults aged 40 years or older with COPD. The primary endpoint was all-cause mortality, with Kaplan-Meier survival curves and restricted cubic splines applied to illustrate the relationship between leukocyte-based inflammatory markers and mortality. The analysis was conducted in 2023. Results: Our analysis included 1,715 COPD participants, representing 6,976,232 non-institutionalized US residents [weighted mean age (SE), 62.09 (0.28) years; range, 40-85 years]. Among the participants, men constituted 50.8% of the population, and the weighted mean follow-up duration was 84.9 months. In the ICS use group, the weighted proportion of participants over 70 years old was significantly higher compared with the non-ICS use group (31.39% vs 25.52%, p < 0.0001). The adjusted hazard ratios for all-cause mortality related to neutrophil counts, lymphocyte counts, and NLR were 1.10 [95% confidence interval (CI), 1.04-1.16, p < 0.001], 0.83 (95% CI, 0.71-0.98; p = 0.03), and 1.10 (95% CI, 1.05-1.15; p < 0.0001), respectively. Optimal ICS response was linked with higher levels of eosinophil count (≥240 cells/µL), neutrophil count (≥3,800 cells/µL), NLR (≥4.79), and lower levels of lymphocyte count (<2,400 cells/µL). Conclusion: Adjusted baseline neutrophil, lymphocyte counts, and NLR serve as independent risk factors for all-cause mortality in patients with COPD. Further, ICS application appears to mitigate mortality risk, particularly when NLR levels reach 4.79 or higher, underlining the importance of ICS in COPD management. Graphical abstract: Inhaled Corticosteroid Use in COPD: A Comparative Analysis of Leukocyte-based Inflammatory Markers and Mortality Outcomes Based on NHANES Data (1999-2018).

Flavonoid Biosynthesis Pathway May Indirectly Affect Outcrossing Rate of Cytoplasmic Male-Sterile Lines of Soybean.

(1) Background: Cytoplasmic male sterility (CMS) is important for exploiting heterosis. Soybean (Glycine max L.) has a low outcrossing rate that is detrimental for breeding sterile lines and producing hybrid seeds. Therefore, the molecular mechanism controlling the outcrossing rate should be elucidated to increase the outcrossing rate of soybean CMS lines; (2) Methods: The male-sterile soybean lines JLCMS313A (with a high outcrossing rate; HL) and JLCMS226A (with a low outcrossing rate; LL) were used for a combined analysis of the transcriptome (RNA-seq) and the targeted phenol metabolome; (3) Results: The comparison between HL and LL detected 5946 differentially expressed genes (DEGs) and 81 phenolic metabolites. The analysis of the DEGs and differentially abundant phenolic metabolites identified only one common KEGG pathway related to flavonoid biosynthesis. The qRT-PCR expression for eight DEGs was almost consistent with the transcriptome data. The comparison of the cloned coding sequence (CDS) regions of the SUS, FLS, UGT, and F3H genes between HL and LL revealed seven single nucleotide polymorphisms (SNPs) only in the F3H CDS. Moreover, five significant differentially abundant phenolic metabolites between HL and LL were associated with flavonoid metabolic pathways. Finally, on the basis of the SNPs in the F3H CDS, one derived cleaved amplified polymorphic sequence (dCAPS) marker was developed to distinguish between HL and LL soybean lines; (4) Conclusions: The flavonoid biosynthesis pathway may indirectly affect the outcrossing rate of CMS sterile lines in soybean.

Dosage optimization of tacrolimus based on the glucocorticoid dose and pharmacogenetics in adult patients with systemic lupus erythematosus.

BACKGROUND: The purpose of the study was to develop a genotype-incorporated population pharmacokinetic (PPK) model of tacrolimus (TAC) in adults with systemic lupus erythematosus (SLE) to investigate the factors influencing TAC pharmacokinetics and to develop an individualized dosing regimen based on the model. In addition, a non-genotype-incorporated model was also established to assess its predictive performance compared to the genotype-incorporated model. METHODS: A total of 365 trough concentrations from 133 adult SLE patients treated with TAC were collected to develop a genotype-incorporated PPK model and a non-genotype-incorporated PPK model of TAC using a nonlinear mixed-effects model (NONMEM). External validation of the two models was performed using data from an additional 29 patients. Goodness-of-fit diagnostic plots, bootstrap method, and normalized predictive distribution error test were used to validate the predictive performance and stability of the final models. The goodness-of-fit of the two final models was compared using the Akaike information criterion (AIC). The dosing regimen was optimized using Monte Carlo simulations based on the developed optimal model. RESULTS: The typical value of the apparent clearance (CL/F) of TAC estimated in the final genotype-incorporated model was 14.3 L h-1 with inter-individual variability of 27.6%. CYP3A5 polymorphism and coadministered medication were significant factors affecting TAC-CL/F. CYP3A5 rs776746 GG genotype carriers had only 77.3% of the TAC-CL/F of AA or AG genotype carriers. Omeprazole reduced TAC-CL/F by 3.7 L h-1 when combined with TAC, while TAC-CL/F increased nonlinearly as glucocorticoid dose increased. Similar findings were demonstrated in the non-genotype-incorporated PPK model. Comparing these two models, the genotype-incorporated PPK model was superior to the non-genotype-incorporated PPK model (AIC = 643.19 vs. 657.425). Monte Carlo simulation based on the genotype-incorporated PPK model indicated that CYP3A5 rs776746 AA or AG genotype carriers required a 1/2-1 fold higher dose of TAC than GG genotype carriers to achieve the target concentration. And as the daily dose of prednisone increases, the dose of TAC required to reach the target concentration increases appropriately. CONCLUSIONS: We developed the first pharmacogenetic-based PPK model of TAC in adult patients with SLE and proposed a dosing regimen based on glucocorticoid dose and CYP3A5 genotype according to the model, which could facilitate individualized dosing for TAC.

Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.

Acute Kidney Injury (AKI), a critical clinical syndrome, has been strongly linked to mitochondrial malfunction. Mitochondria, vital cellular organelles, play a key role in regulating cellular energy metabolism and ensuring cell survival. Impaired mitochondrial function in AKI leads to decreased energy generation, elevated oxidative stress, and the initiation of inflammatory cascades, resulting in renal tissue damage and functional impairment. Therefore, mitochondria have gained significant research attention as a potential therapeutic target for AKI. Mitochondrial dynamics, which encompass the adaptive shifts of mitochondria within cellular environments, exert significant influence on mitochondrial function. Modulating these dynamics, such as promoting mitochondrial fusion and inhibiting mitochondrial division, offers opportunities to mitigate renal injury in AKI. Consequently, elucidating the mechanisms underlying mitochondrial dynamics has gained considerable importance, providing valuable insights into mitochondrial regulation and facilitating the development of innovative therapeutic approaches for AKI. This comprehensive review aims to highlight the latest advancements in mitochondrial dynamics research, provide an exhaustive analysis of existing studies investigating the relationship between mitochondrial dynamics and acute injury, and shed light on their implications for AKI. The ultimate goal is to advance the development of more effective therapeutic interventions for managing AKI.

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia.

BACKGROUND: Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanisms remain unclear. METHODS: An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia patients with delayed methotrexate excretion, with or without acute kidney injury, was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro HK-2 cell assays further verified the candidate metabolites, and explored the mechanisms underlying the nephrotoxicity of methotrexate. RESULTS: Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione was confirmed as a candidate metabolite involved in the toxicity of methotrexate. We further explored the role of glutathione deprivation-induced ferroptosis on methotrexate cytotoxicity, and it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe2+ accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. CONCLUSIONS: Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Natural variation of MS2 confers male fertility and drives hybrid breeding in soybean.

A complete and genetically stable male sterile line with high outcrossing rate is a prerequisite for the development of commercial hybrid soybean. It was reported in the last century that the soybean male sterile ms2 mutant has the highest record with seed set. Here we report the cloning and characterization of the MS2 gene in soybean, which encodes a protein that is specifically expressed in the anther. MS2 functions in the tapetum and microspore by directly regulating genes involved in the biosynthesis of secondary metabolites and the lipid metabolism, which is essential for the formation of microspore cell wall. Through comparison of the field performance with the widely used male sterile mutants in the same genetic background, we demonstrated that the ms2 mutant conducts the best in outcrossing rate and makes it an ideal tool in building a cost-effective hybrid system for soybean.

Development of a UPLC-MS/MS method for simultaneous therapeutic drug monitoring of anti-hepatocellular carcinoma drugs and analgesics in human plasma.

In hepatocellular carcinoma treatment, sorafenib, oxaliplatin, 5-fluorouracil, capecitabine, lenvatinib, and donafenib are first-line drugs; regorafenib, apatinib, and cabozantinib are second-line drugs; and oxycodone, morphine, and fentanyl are commonly used analgesics. However, the high degree of inter- and intra-individual variability in the efficacy and toxicity of these drugs remains an urgent issue. Therapeutic drug monitoring (TDM) is the most reliable technical means for evaluating drug safety and efficacy. Therefore, we developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM of three chemotherapy drugs (5-fluorouracil, oxaliplatin, and capecitabin), six targeted drugs (sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib), and three analgesics (morphine, fentanyl, and oxycodone). We extracted 12 analytes and isotope internal standards (ISs) from plasma samples by magnetic solid phase extraction (mSPE) and separated them using a ZORBAX Eclipse Plus C18 column with water containing 0.1% formic acid and methanol containing 0.1% formic acid as the mobile phase. The analytical performance of our method in terms of sensitivity, linearity, specificity, carryover, precision, limit of quantification, matrix effect, accuracy, dilution integrity, extraction recovery, stability, and crosstalk of all the analytes under different conditions met all the criteria stipulated by the guidelines of the Chinese Pharmacopoeia and U.S. Food and Drug Administration. The response function was estimated at 10.0-10 000.0 ng/mL for sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib, and 20.0-20 000.0 ng/mL for 5-fluorouracil, oxaliplatin, capecitabin, morphine, fentanyl, and oxycodone, with a correlation of > 0.9956 for all compounds. The precision and accuracy of all analytes were < 7.21% and 5.62%, respectively. Our study provides empirical support for a simple, reliable, specific, and suitable technique for clinical TDM and pharmacokinetics.

Population pharmacokinetic analyses of tacrolimus in non-transplant patients: a systematic review.

BACKGROUND AND OBJECTIVES: Tacrolimus (TAC) has been increasingly used in patients with non-transplant settings. Because of its large between-subject variability, several population pharmacokinetic (PPK) studies have been performed to facilitate individualized therapy. This review summarized published PPK models of TAC in non-transplant patients, aiming to clarify factors affecting PKs of TAC and identify the knowledge gap that may require further research. METHODS: The PubMed, Embase databases, and Cochrane Library, as well as related references, were searched from the time of inception of the databases to February 2023, to identify TAC population pharmacokinetic studies modeled in non-transplant patients using a non-linear mixed-effects modeling approach. RESULTS: Sixteen studies, all from Asian countries (China and Korea), were included in this study. Of these studies, eleven and four were carried out in pediatric and adult patients, respectively. One-compartment models were the commonly used structural models for TAC. The apparent clearance (CL/F) of TAC ranged from 2.05 to 30.9 L·h-1 (median of 14.9 L·h-1). Coadministered medication, genetic factors, and weight were the most common covariates affecting TAC-CL/F, and variability in the apparent volume of distribution (V/F) was largely explained by weight. Coadministration with Wuzhi capsules reduced CL/F by about 19 to 43%. For patients with CYP3A5*1*1 and *1*3 genotypes, the CL/F was 39-149% higher CL/F than patients with CYP3A5*1*1. CONCLUSION: The optimal TAC dosage should be adjusted based on the patient's co-administration, body weight, and genetic information (especially CYP3A5 genotype). Further studies are needed to assess the generalizability of the published models to other ethnic groups. Moreover, external validation should be frequently performed to improve the clinical practicality of the models.

Integrated Analyses of the Expression and Prognostic Value of EPHB6 in Cervical Cancer and Its Correlation with Immune Infiltrates.

Among women, cervical cancer (CC) ranks as the third most frequent form of carcinoma and the fourth greatest cancer-related cause of deaths. There is increasing evidence that points to the dysregulation of EPH receptor B6 (EPHB6) in various cancers. On the other hand, neither the expression nor the function of EPHB6 in CC has been researched. In the first part of this investigation, we analyzed the data from the TCGA and discovered that the level of EPHB6 was much lower in CC tissues than in normal cervical tissues. ROC assays revealed that high EPHB6 expression had an AUC value of 0.835 for CC. The survival study revealed that both the overall and disease-specific survivals in this condition were considerably lower among patients who had a low EPHB6 level compared to those who had a high EPHB6 level. It is important to note that the multivariate COX regression analysis indicated that the expression of EPHB6 was an independent predictive factor. In addition to this, the C-indexes and calibration plots of a nomogram derived from multivariate assays revealed an accurate prediction performance among patients with CC. Immune infiltration analysis indicated that the expression of EPHB6 was positively associated with the levels of Tcm, TReg, B cells, T cells, iDC, T helper cells, cytotoxic cells, and DC, while negatively associated with NK CD56bright cells and neutrophils. In summary, the downregulation of EPHB6 was strongly linked to a more aggressive clinical development of CC, suggesting its potential utility as a diagnostic and therapeutic target in CC.

Iron metabolism-related indicators as predictors of the incidence of acute kidney injury after cardiac surgery: a meta-analysis.

BACKGROUND: Some studies have found that ferroptosis plays an important role in the incidence of acute kidney injury (AKI) after cardiac surgery. However, whether iron metabolism-related indicators can be used as predictors of the incidence of AKI after cardiac surgery remains unclear. OBJECTIVES: We aimed to systematically evaluate whether iron metabolism-related indicators can be used as predictors of the incidence of AKI after cardiac surgery via meta-analysis.Search methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were searched from January 1971 to February 2023 to identify prospective observational and retrospective observational studies examining iron metabolism-related indicators and the incidence of AKI after cardiac surgery among adults.Data Extraction and Synthesis: The following data were extracted by two independent authors (ZLM and YXY): date of publication, first author, country, age, sex, number of included patients, iron metabolism-related indicators, outcomes of patients, patient types, study types, sample, and specimen sampling time. The level of agreement between authors was determined using Cohen's κ value. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of studies. Statistical heterogeneity across the studies was measured by the I2 statistic. The standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect size measures. Meta-analysis was performed using Stata 15. RESULTS: After applying the inclusion and exclusion criteria, 9 articles on iron metabolism-related indicators and the incidence of AKI after cardiac surgery were included in this study. Meta-analysis revealed that after cardiac surgery, baseline serum ferritin (µg/L) (I2 = 43%, fixed effects model, SMD = -0.3, 95% CI:-0.54 to -0.07, p = 0.010), preoperative and 6-hour postoperative fractional excretion (FE) of hepcidin (%) (I2 = 0.0%, fixed effects model, SMD = -0.41, 95% CI: -0.79 to -0.02, p = 0.038; I2 = 27.0%, fixed effects model, SMD = -0.49, 95% CI: -0.88 to -0.11, p = 0.012), 24-hour postoperative urinary hepcidin (µg/L) (I2 = 0.0%, fixed effects model, SMD = -0.60, 95% CI: -0.82 to -0.37, p < 0.001) and urine hepcidin/urine creatinine ratio (µg/mmoL) (I2 = 0.0%, fixed effects model, SMD = -0.65, 95% CI: -0.86 to -0.43, p < 0.001) were significantly lower in patients who developed to AKI than in those who did not. CONCLUSION: After cardiac surgery, patients with lower baseline serum ferritin levels (µg/L), lower preoperative and 6-hour postoperative FE of hepcidin (%), lower 24-hour postoperative hepcidin/urine creatinine ratios (µg/mmol) and lower 24-hour postoperative urinary hepcidin levels (µg/L) are more likely to develop AKI. Therefore, these parameters have the potential to be predictors for AKI after cardiac surgery in the future. In addition, there is a need for relevant clinical research of larger scale and with multiple centers to further test these parameters and prove our conclusion.Trial Registration: PROSPERO identifier: CRD42022369380.

High-yielding nitrate transporter cultivars also mitigate methane and nitrous oxide emissions in paddy.

Development of high yield rice varieties is critical to ensuring global food security. However, the emission of greenhouse gases (GHG) such as Methane (CH4) and Nitrous oxide (N2O) from paddy fields threatens environmental sustainability. In this study, we selected overexpressed high-affinity nitrate transporters (NRT2.3 along with their partner protein NAR2.1) cultivars, which are effective nitrogen use efficient transgenic lines pOsNAR2.1: OsNAR2.1 (Ox2) and p35S:OsNRT2.3b (O8). We used high (270 kg N/ha) and low (90 kg N/ha) nitrogen (N) fertilizers in paddy fields to evaluate morphophysiological traits, including GHG emission. We found that Ox2 and O8 reduced CH4 emissions by 40% and 60%, respectively, compared to their wild type (WT). During growth stages, there was no consistent N2O discharge pattern between WT and transgenics (Ox2, O8) in low and high N application. However, total cumulative N2O in a cropping season reduced in O8 and increased in Ox2 cultivars, compared to WT. Root aerenchyma formation reduced by 30-60% in transgenic lines. Methanogens like mcrA in low and high N were also reduced by up to 50% from rhizosphere of Ox2 and O8. However, the nitrifying bacterial population such as nosZ reduced in both transgenics significantly, but nirK and nirS did not show a consistent variation. The high yield of transgenic rice with limited aerenchyma mitigates the discharge of CH4 and N2O by reducing root exudates that provide substrates for GHG. Our results improve understanding for breeders to serve the purpose of sustainable development.