Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia.

Eltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of eltrombopag. Twenty-three AA children with an average age of 7.9 (range of 3.0-14.0) years were enrolled. The response (complete and partial response) rate was 12.5%, 50.0%, and 100.0% after 3, 6, and 12 months in patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were used to build the PPK model. Body weight was the only covariate for apparent clearance (CL/F) and volume of distribution. The allele-T carrier of adenosine triphosphate-binding cassette transporter G2 was found to increase eltrombopag's clearance. However, when normalized by weight, the clearance between the wild-type and variant showed no statistical difference. In patients with response, children with NSAA exhibited lower area under the curve from time zero to infinity, higher CL/F, and higher weight-adjusted CL/F than those with SAA or VSAA. However, the differences were not statistically significant. The results may support further individualized treatment of eltrombopag in children with AA.

Subgrouping testicular germ cell tumors based on immunotherapy and chemotherapy associated lncRNAs.

Testicular germ cell tumors (TGCT) are the most common reproductive system malignancies in men aged 15-44 years, accounting for 95 % of all testicular tumors. Our previous studies have been shown that long non-coding RNAs (lncRNAs), such as LINC00313, TTTY14 and RFPL3S, were associated with development of TGCT. Subgrouping TGCT according to differential expressed lncRNAs and immunological characteristics is helpful to comprehensively describe the characteristics of TGCT and implement precise treatment. In this study, the TGCT transcriptome data in The Cancer Genome Atlas Program (TCGA) database was used to perform consensus clustering analysis to construct a prognostic model for TGCT. TGCT was divided into 3 subtypes C1, C2, and C3 based on the differentially expressed lncRNAs. C1 subtype was sensitive to chemotherapy drugs, while the C2 subtype was not sensitive to chemotherapy drugs, and C3 subtype may benefit from immunotherapy. We defined the C1 subtype as epidermal progression subtype, the C2 subtype as mesenchymal progression subtype, and the C3 subtype as T cell activation subtype. Subgrouping based on differentially expressed genes (DEGs) and immunological characteristics is helpful for the precise treatment of TGCT.

Single Cell Map of Human Azoospermia Testis Caused by Cyclophosphamide Chemotherapy.

Chemotherapeutic drugs will affect the process of spermatogenesis. However, most current studies on the effects of chemotherapeutic drugs on spermatogenesis are based on mouse models, with a shortage of human body evidence. In addition, the mechanism of chemotherapeutic drugs causing spermatogenesis disorder is not clear. Therefore, we have collected the testicular tissues of an inguinal-lipoma patient whose testes were resected after chemotherapy and a patient who had normal spermatogenesis disorder and underwent single-nucleus RNA sequencing (snRNA-Seq). After quality control, we obtained a total of 27,957 high-quality cells, including 18,612 normal cells and 9,345 drug-treated cells, which were all used in analyzing the mechanism of chemotherapeutic drugs causing spermatogenesis disorder. This study has provided data resources and references for exploring the mechanism of chemotherapeutic drugs causing spermatogenesis disorder with the insight of protecting the spermatogenic abilities of male tumor patients receiving chemotherapy.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Compressive buttress compared with off-axial screw fixation for vertical femoral neck fractures in young adults: a prospective, randomized controlled trial.

BACKGROUND: To compare the clinical outcomes of compressive buttress screw (CBS) fixation, a novel screw fixation strategy, to off-axial screw fixation (off-axial partial threaded cannulated screw, OPTCS) for vertical femoral neck fractures (FNFs) in young adults. METHODS: A total of 146 adults younger than 55 years old with high-energy Pauwels type III FNFs were randomized to receive CBS fixation or OPTCS fixation. Primary outcomes were complication rates, including fixation failure, fracture nonunion, and avascular necrosis of the femoral head (ANFH) at 24 months after treatment. Fixation loosening, femoral neck shortening and varus collapse, patient function and quality of life using the Harris hip score (HHS), and EuroQol-5 dimensional-5 levels (EQ-5D-5L) questionnaire (including EQ-5D-5L and EQ-VAS) were assessed as secondary outcomes at 24 months. RESULTS: CBS and OPTCS fixation groups were similar with regard to demographics at baseline. At 24 months, patients in the CBS fixation cohort had a significantly lower rate of fixation failure (10.5% vs. 25.0%, p = 0.041) and fracture nonunion (1.8% vs. 18.3%, p = 0.003) compared with patients who received OPTCS fixation. There was no difference in rate of ANFH (7.0% vs. 11.7%, p = 0.389) between groups. Additionally, patients managed with CBS fixation showed significantly less fixation loosening (19.3% vs. 58.3%, p < 0.001), less severe femoral neck shortening and varus collapse (10.5% vs. 25.0%, p = 0.007), higher HHS (93 vs. 83, p = 0.001) and more excellent grade (68.4% vs. 36.7%, p = 0.008), higher EQ-5D-5L (0.814 vs, 0.581, p < 0.001) and EQ-VAS (85 vs. 80, p = 0.002). CONCLUSION: CBS screw fixation confers significantly lower complication rate in addition to higher functional and quality of life outcomes for young adults with high-energy FNF compared with OPTCS fixation. TRIAL REGISTRATION: This prospective, randomized controlled trial was approved by the institutional review board of our center, Ethics Committee of Shanghai sixth people's Hospital, and registered at www.chictr.org.cn (Approval Number: ChiCTR1900026283; Registered 29 September 2019-Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=43164 ).

Long-term storage modifies the microRNA expression profile of cryopreserved human semen.

The global practice of cryopreservation of human semen is commonplace in Assisted Reproductive Technology (ART) labs and sperm banks. However, information on the effects of long-term cryopreservation on semen is limited to clinical data summaries and descriptions. For this study, we prepared 4 semen specimens of fresh semen, 4 specimens cryostored for at least 1 year, 3 specimens cryostored for at least 5 years, 4 specimens cryostored for at least 10 years, and 3 specimens cryostored for at least 15 years. Total RNA was extracted from each sample, amplified, labeled, and mapped to the known primary microRNA (miRNA) in the miRBase database, enabling the prediction of novel miRNAs. We found that cryopreservation can lead to changes in miRNA expression, and with the increase in storage time, these changes became more pronounced. Meanwhile, the expression of let-7d-3p, let-7c-5p and let-7i-3p miRNAs changed dynamically over cryostorage time in frozen-thawed human sperm. Furthermore, we analyzed the time-dependent dynamics of cryostorage-expressed miRNAs and their target mRNAs and found that half of the target genes were expressed in oocytes. These intersection genes were mainly enriched in cancer and cytoskeletal signaling pathways. Our findings showed that the miRNA expression profile of cryopreserved human semen is modified by long-term storage. Furthermore, as the storage time increases, the impact on human sperm becomes more pronounced in terms of miRNAs, which may have an effect on subsequent fertilization and embryonic development.

Population pharmacokinetics of antibacterial agents in the older population: a literature review.

INTRODUCTION: Older individuals face an elevated risk of developing bacterial infections. The optimal use of antibacterial agents in this population is challenging because of age-related physiological alterations, changes in pharmacokinetics (PK) and pharmacodynamics (PD), and the presence of multiple underlying diseases. Therefore, population pharmacokinetics (PPK) studies are of great importance for optimizing individual treatments and prompt identification of potential risk factors. AREA COVERED: Our search involved keywords such as 'elderly,' 'old people,' and 'geriatric,' combined with 'population pharmacokinetics' and 'antibacterial agents.' This comprehensive search yielded 11 categories encompassing 28 antibacterial drugs, including vancomycin, ceftriaxone, meropenem, and linezolid. Out of 127 studies identified, 26 (20.5%) were associated with vancomycin, 14 (11%) with meropenem, and 14 (11%) with piperacillin. Other antibacterial agents were administered less frequently. EXPERT OPINION: PPK studies are invaluable for elucidating the characteristics and relevant factors affecting the PK of antibacterial agents in the older population. Further research is warranted to develop and validate PPK models for antibacterial agents in this vulnerable population.

Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment.

Seminoma is the most common malignant solid tumor in 14 to 44 year-old men. However, its molecular features and tumor microenvironment (TME) is largely unexplored. Here, we perform a series of studies via genomics profiling (single cell multi-omics and spatial transcriptomics) and functional examination using seminoma samples and a seminoma cell line. We identify key gene expression programs share between seminoma and primordial germ cells, and further characterize the functions of TFAP2C in promoting tumor invasion and migration. We also identify 15 immune cell subtypes in TME, and find that subtypes with exhaustion features were located closer to the tumor region through combined spatial transcriptome analysis. Furthermore, we identify key pathways and genes that may facilitate seminoma disseminating beyond the seminiferous tubules. These findings advance our knowledge of seminoma tumorigenesis and produce a multi-omics atlas of in situ human seminoma microenvironment, which could help discover potential therapy targets for seminoma.

CSNK1G2-AS1 promotes metastasis, colony formation and serves as a biomarker in testicular germ cell tumor cells.

Background/Aim: Some long non-coding RNAs (lncRNAs) have been found to significantly participate in the progression of TGCTs. In comparison to the normal testis, the TGCT tissues showed significantly decreased CSNK1G2-AS1 expression, however, its effect on TGCTs and its mechanism are still unclear. The aim of this study is to investigate the effect of CSNK1G2-AS1 on TGCTs and explore the mechanism underlying its effect on TGCTs. Materials and Methods: In this study, to evaluate the expression of CSNK1G2-AS1 in tissue samples from TGCTs, the UCSC and GEPIA databases were applied and qRT-PCR was conducted. The Kaplan-Meier Plotter was applied to analyze the correlation between CSNK1G2-AS1 methylation levels and the prognosis of TGCTs patients. The assays of MTS, clone formation, transwell, and flow cytometry were performed to investigate the effect of CSNK1G2-AS1 overexpression on the proliferation, metastasis, and apoptosis of TGCT cells, respectively. Finally, western blotting was conducted to determine the expressions of the proteins associated with EMT and AKT. Results: Our study first found that, compared to the normal testis, TGCTs tissue showed significantly decreased CSNK1G2-AS1 expression, and hypomethylation of CSNK1G2-AS1 was significantly correlated with a better prognosis with TGCTs patients. In vitro, we found that overexpression of CSNK1G2-AS1 dramatically promoted the clone formation, invasion, and migration of TGCT cells, but inhibited apoptosis. And CSNK1G2-AS1 overexpression significantly decreased the expression of EMT-associated proteins ZO-1 but increased the expression and phosphorylation of AKT. Conclusions: CSNK1G2-AS1 may play an essential role in the pathogenesis and metastasis of TGCTs through the EMT- and AKT-mediated signal pathways.

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

TNFSF10, an autophagy related gene, was a prognostic and immune infiltration marker in skin cutaneous melanoma.

Autophagy exerts a pivotal effect on skin cutaneous melanoma (SKCM). This study was aimed to investigate the expression of autophagy related genes (ARGs) in SKCM as well as its clinical value. Differentially expressed (DE) ARGs were downloaded from the intersection of SKCM data in GEPIA2 database and ARGs in Human Autophagy Database (HADB) database, and were verified in SKCM datasets GSE46517 and GSE15605. DE ARGs were enriched by Metascape online tools. According to GEPIA2 database, tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10) was identified as a closely related factor and prognostic marker of SKCM. Then the correlation analysis of clinicopathological characteristics between TNFSF10 and SKCM was completed by several online tools such as TISCH, HPA, BEST and qRT-PCR. Subsequently, we investigated TNFSF10 related functions and signal pathways with LinkedOmics online tool, and immune infiltration using Assistant for Clinical Bioinformatics online tool. Furthermore, correlation analysis between TNFSF10 expression and immunotherapy response was performed by TIDE algorithm and BEST online tool. And Kaplan-Meier Plotter was used to assessing the prognosis of SKCM patients receiving immunotherapy. Finally, the correlation analysis among TNFSF10 methylation, TNFSF10 expression and patient prognosis was completed by the DiseaseMeth version 2.0, UCSC XENA and qRT-PCR. ARGs are DE in SKCM and participate in the ERBB signaling pathway, as well as the processing and presentation of antigens. Moreover, TNFSF10's expression along with methylation expression were significantly associated with the prognosis. Low expression of TNFSF10 was associated with malignant clinicopathological features, lower immune signal activity and lower immunocytes abundance in patients with SKCM. As an ARG, TNFSF10 has a potential capacity in predicting the prognosis of SKCM patients, meanwhile, may be a novel immunotherapy marker for SKCM.

Single-cell RNA sequencing technology in human spermatogenesis: Progresses and perspectives.

Spermatogenesis, a key part of the spermiation process, is regulated by a combination of key cells, such as primordial germ cells, spermatogonial stem cells, and somatic cells, such as Sertoli cells. Abnormal spermatogenesis can lead to azoospermia, testicular tumors, and other diseases related to male infertility. The application of single-cell RNA sequencing (scRNA-seq) technology in male reproduction is gradually increasing with its unique insight into deep mining and analysis. The data cover different periods of neonatal, prepubertal, pubertal, and adult stages. Different types of male infertility diseases including obstructive and non-obstructive azoospermia (NOA), Klinefelter Syndrome (KS), Sertoli Cell Only Syndrome (SCOS), and testicular tumors are also covered. We briefly review the principles and application of scRNA-seq and summarize the research results and application directions in spermatogenesis in different periods and pathological states. Moreover, we discuss the challenges of applying this technology in male reproduction and the prospects of combining it with other technologies.

Machine Learning: A New Approach for Dose Individualization.

The application of machine learning (ML) has shown promising results in precision medicine due to its exceptional performance in dealing with complex multidimensional data. However, using ML for individualized dosing of medicines is still in its early stage, meriting further exploration. A systematic review of study designs and modeling details of using ML for individualized dosing of different drugs was performed. We have summarized the status of the study populations, predictive targets, and data sources for ML modeling, the selection of ML algorithms and features, and the evaluation and validation of their predictive performance. We also used the Prediction model Risk of Bias Assessment Tool (PROBAST) to assess the risk of bias of included studies. Currently, ML can be used for both a priori and a posteriori dose selection and optimization, and it can also assist the implementation of therapeutic drug monitoring. However, studies are mainly focused on drugs with narrow therapeutic windows, predominantly immunosuppressants (N = 23, 35.9%) and anti-infectives (N = 21, 32.8%), and there is currently only very limited attention for special populations, such as children (N = 22, 34.4%). Most studies showed poor methodological quality and a high risk of bias. The lack of external validation and clinical utility evaluation currently limits the further clinical implementation of ML for dose individualization. We therefore have proposed several ways to improve the clinical relevance of the studies and facilitate the translation of ML models into clinical practice.

Polymer Chainmail: Steric Hindrance and Charge Compensation of Anion-Doped PEDOT to Boost Stress Deformation of Compressible Supercapacitor.

Conducting polymers with high theoretical capacitance and deformability are among the optimal candidates for compressible supercapacitor electrode materials. However, achieving both mechanical and electrochemical stabilities in a single electrode remains a great challenge. To address this issue, the "Polymer Chainmail" is proposed with reversible deformation capability and enhances stability because of the steric hindrance and charge compensation effect of doped anions. As a proof of concept, four common anions are selected as dopants for Poly(3,4-ethylenedioxythiophene) (PEDOT), and their effects on the adsorption and diffusion of H+ on PEDOT are verified using density functional theory calculations. Owing to the film formation effect, the PF 6 - ${{\rm{PF}}_6^- }$ doped PEDOT/nitrogen-doped carbon foam exhibits good mechanical properties. Furthermore, the composite demonstrates excellent rate performance and stability due to suitable anion doping. This finding provides new insights into the preparation of electrochemically stable conductive polymer-based compressible electrode materials.

Circ_0003356 suppresses gastric cancer growth through targeting the miR-668-3p/SOCS3 axis.

BACKGROUND: Circular RNAs (circRNAs) have attracted extensive attention as therapeutic targets in gastric cancer (GC). Circ_0003356 is known to be downregulated in GC tissues, but its cellular function and mechanisms remain undefined. AIM: To investigate the role of circ_0003356 in GC at the molecular and cellular level. METHODS: Circ_0003356, miR-668-3p, and SOCS3 expression were assessed via quantitative real time-polymerase chain reaction (qRT-PCR). Wound healing, EdU, CCK-8, flow cytometry and transwell assays were used to analyze the migration, proliferation, viability, apoptosis and invasion of GC cells. The subcellular localization of circ_0003356 was monitored using fluorescence in situ hybridization. The interaction of circ_0003356 with miR-668-3p was confirmed using RIP-qRT-PCR, RNA pull-down, and dual luciferase reporter assays. We observed protein levels of genes via western blot. We injected AGS cells into the upper back of mice and performed immunohistochemistry staining for examining E-cadherin, N-cadherin, Ki67, and SOCS3 expressions. TUNEL staining was performed for the assessment of apoptosis in mouse tumor tissues. RESULTS: Circ_0003356 and SOCS3 expression was downregulated in GC cells, whilst miR-668-3p was upregulated. Exogenous circ_0003356 expression and miR-668-3p silencing suppressed the migration, viability, proliferation, epithelial to mesenchy-mal transition (EMT) and invasion of GC cells and enhanced apoptosis. Circ_0003356 overexpression impaired tumor growth in xenograft mice. Targeting of miR-668-3p by circ_0003356 was confirmed through binding assays and SOCS3 was identified as a downstream target of miR-668-3p. The impacts of circ_0003356 on cell proliferation, apoptosis, migration, invasion and EMT were reversed by miR-668-3p up-regulation or SOCS3 down-regulation in GC cells. CONCLUSION: Circ_0003356 impaired GC development through its interaction with the miR-668-3p/SOCS3 axis.

Experimental Revelation of Surface and Bulk Lattices in Faceted Cu2 O Crystals.

Semiconductor crystals have generally shown facet-dependent electrical, photocatalytic, and optical properties. These phenomena have been proposed to result from the presence of a surface layer with bond-level deviations. To provide experimental evidence of this structural feature, synchrotron X-ray sources are used to obtain X-ray diffraction (XRD) patterns of polyhedral cuprous oxide crystals. Cu2 O rhombic dodecahedra display two distinct cell constants from peak splitting. Peak disappearance during slow Cu2 O reduction to Cu with ammonia borane differentiates bulk and surface layer lattices. Cubes and octahedra also show two peak components, while diffraction peaks of cuboctahedra are comprised of three components. Temperature-varying lattice changes in the bulk and surface regions also show shape dependence. From transmission electron microscopy (TEM) images, slight plane spacing deviations in surface and inner crystal regions are measured. Image processing provides visualization of the surface layer with depths of about 1.5-4 nm giving dashed lattice points instead of dots from atomic position deviations. Close TEM examination reveals considerable variation in lattice spot size and shape for different particle morphologies, explaining why facet-dependent properties are emerged. Raman spectrum reflects the large bulk and surface lattice difference in rhombic dodecahedra. Surface lattice difference can change the particle bandgap.

Preparation of fat substitute based on maize starch hydrolysates and application in reduced-fat acidified milk gel.

Reduced-fat food has become a popular choice among contemporary consumers. This study aims to develop a starch-based fat substitute and incorporate it into reduced-fat milk gel acidified with glucono-δ-lactone (GDL) to achieve similar rheological properties as a full-fat gel. The gel properties of the fat substitute were assessed. The study examined the rheological properties, syneresis, textural properties and microstructure of acidified milk gels while also monitoring acidification process. Starch hydrolysates with low dextrose equivalent (DE) (<5.1 %) can serve as an effective fat substitute due to their excellent gelling properties The rheological and textural properties of the reduced-fat acidified milk gel with DE at 3.1 % of starch hydrolysate and 30 % fat substitution are similar to those of the full-fat milk gel. The syneresis and confocal laser scanning microscopy (CLSM) results indicated that the microstructure of the reduced-fat acidified milk gel was similar to the full-fat version. Moreover, the sensory properties of the reduced-fat acidified milk gel were acceptable when the DE was 3.1 %, and 30 % fat was replaced. In our study, we utilized hydrolyzed starch to produce reduced-fat acidified milk gels, which could potentially be used in the development of reduced-fat yogurt formulations.

Use of Machine Learning for Dosage Individualization of Vancomycin in Neonates.

BACKGROUND AND OBJECTIVE: High variability in vancomycin exposure in neonates requires advanced individualized dosing regimens. Achieving steady-state trough concentration (C0) and steady-state area-under-curve (AUC0-24) targets is important to optimize treatment. The objective was to evaluate whether machine learning (ML) can be used to predict these treatment targets to calculate optimal individual dosing regimens under intermittent administration conditions. METHODS: C0 were retrieved from a large neonatal vancomycin dataset. Individual estimates of AUC0-24 were obtained from Bayesian post hoc estimation. Various ML algorithms were used for model building to C0 and AUC0-24. An external dataset was used for predictive performance evaluation. RESULTS: Before starting treatment, C0 can be predicted a priori using the Catboost-based C0-ML model combined with dosing regimen and nine covariates. External validation results showed a 42.5% improvement in prediction accuracy by using the ML model compared with the population pharmacokinetic model. The virtual trial showed that using the ML optimized dose; 80.3% of the virtual neonates achieved the pharmacodynamic target (C0 in the range of 10-20 mg/L), much higher than the international standard dose (37.7-61.5%). Once therapeutic drug monitoring (TDM) measurements (C0) in patients have been obtained, AUC0-24 can be further predicted using the Catboost-based AUC-ML model combined with C0 and nine covariates. External validation results showed that the AUC-ML model can achieve an prediction accuracy of 80.3%. CONCLUSION: C0-based and AUC0-24-based ML models were developed accurately and precisely. These can be used for individual dose recommendations of vancomycin in neonates before treatment and dose revision after the first TDM result is obtained, respectively.

[Latest Findings on the Function of Immune Metabolism in Tumor Immunity].

Metabolic reprogramming, an important hallmark of cancer, helps cancer achieve rapid proliferation. Metabolic changes in tumors regulate multiple metabolic pathways of immune cells, thereby suppressing antitumor immunity. Recent studies have been focused on in-depth investigation into the changes in the metabolism of glucose, amino acids, and lipids. Researchers have also conducted in-depth exploration of the interactive metabolic regulation of tumor cells and immune cells. Targeting various metabolic mechanisms while combining available anti-tumor therapies and enhancing the anti-tumor effects of immunotherapy by satisfying the metabolic demands of immune cells has offered new perspectives for therapies targeting the immune metabolism of tumors and enhancing anti-tumor immune responses. Studies on novel immune checkpoint molecules and cellular immunotherapies are also ongoing. Herein, we reviewed the latest findings on the mechanisms of immune metabolism underlying tumor immunosuppression and their application in immunotherapy. We also suggested some ideas for the future development of the regulation of immune metabolism.

DNA hypomethylation and upregulated LINC00518 acts as a promoter and biomarker in head and neck squamous cell carcinoma.

Background: LINC00518 acts as an oncogene in several cancers, but its function in head and neck squamous cell carcinoma (HNSCC) remains unclear. Materials & methods: The expression and methylation status of LINC00518 were analyzed by reviewing public databases. The ceRNA network and the relationship with tumor immunity of LINC00518 were analyzed using online tools and in vitro studies. Results: Upregulated LINC00518 was associated with poor clinicopathological characteristics of HNSCC. Silencing LINC00518 significantly inhibited the migration of HNSCC cells. LINC00518 might positively regulate HMGA2 via the ceRNA mechanism. Additionally, LINC00518 was negatively correlated with various immune cells and immunotherapy markers. Moreover, the upregulation of LINC00518 in HNSCC may be due to DNA hypomethylation. Conclusion: LINC00518 may be a potential biomarker and therapeutic target for HNSCC.