scCancer2: data-driven in-depth annotations of the tumor microenvironment at single-level resolution.

SUMMARY: Single-cell RNA-seq (scRNA-seq) is a powerful technique for decoding the complex cellular compositions in the tumor microenvironment (TME). As previous studies have defined many meaningful cell subtypes in several tumor types, there is a great need to computationally transfer these labels to new datasets. Also, different studies used different approaches or criteria to define the cell subtypes for the same major cell lineages. The relationships between the cell subtypes defined in different studies should be carefully evaluated. In this updated package scCancer2, designed for integrative tumor scRNA-seq data analysis, we developed a supervised machine learning framework to annotate TME cells with annotated cell subtypes from 15 scRNA-seq datasets with 594 samples in total. Based on the trained classifiers, we quantitatively constructed the similarity maps between the cell subtypes defined in different references by testing on all the 15 datasets. Secondly, to improve the identification of malignant cells, we designed a classifier by integrating large-scale pan-cancer TCGA bulk gene expression datasets and scRNA-seq datasets (10 cancer types, 175 samples, 663 857 cells). This classifier shows robust performances when no internal confidential reference cells are available. Thirdly, scCancer2 integrated a module to process the spatial transcriptomic data and analyze the spatial features of TME. AVAILABILITY AND IMPLEMENTATION: The package and user documentation are available at http://lifeome.net/software/sccancer2/ and https://doi.org/10.5281/zenodo.10477296.

Pre-Configured Error Pattern Ordered Statistics Decoding for CRC-Polar Codes.

In this paper, we propose a pre-configured error pattern ordered statistics decoding (PEPOSD) algorithm and discuss its application to short cyclic redundancy check (CRC)-polar codes. Unlike the traditional OSD that changes the most reliable independent symbols, we regard the decoding process as testing the error patterns, like guessing random additive noise decoding (GRAND). Also, the pre-configurator referred from ordered reliability bits (ORB) GRAND can better control the range and testing order of EPs. An offline-online structure can accelerate the decoding process. Additionally, we also introduce two orders to optimize the search order for testing EPs. Compared with CRC-aided OSD and list decoding, PEPOSD can achieve a better trade-off between accuracy and complexity.

Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

AIMS: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. METHODS: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesize available evidence. A multicentre cross-sectional study was conducted using questionnaires to evaluate patients' perception and willingness concerning individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. RESULTS: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to administration (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), and management of toxicities. Of these, 12 are strong recommendations. CONCLUSIONS: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX administration to health care providers.

Bioanalytical strategies in drug discovery and development.

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs.

Severe toxic effects of low-dose methotrexate treatment for placenta accreta in a patient with methylenetetrahydrofolate reductase mutations.

WHAT IS KNOWN AND OBJECTIVE: Low-dose methotrexate (LDMTX) has been widely used for many decades in clinical settings, with good safety profiles compared with those of high-dose methotrexate. LDMTX is also used as one of the off-label conservative therapies in treating placenta accreta (PA). Until now, only a few mild adverse drug reactions (ADRs) have been published after short-term use of LDMTX, and no severe cases have been reported. CASE SUMMARY: We present a case of a 30-year-old female who developed acute severe oral ulcerative mucositis with degree IV myelosuppression and degree III hepatic injury, after three doses of LDMTX to treat placenta accrete. The symptoms gradually improved after leucovorin rescue and supportive treatments. WHAT IS NEW AND CONCLUSION: The present case provides the first severe ADR report for the short-term use of LDMTX for treating PA, indicating that potentially life-threatening complications can also occur when using LDMTX. Early recognition and immediate leucovorin rescue could result in a favourable outcome.

Chitinophaga silvisoli sp. nov., isolated from forest soil.

A Gram-stain-negative, rod-shaped and aerobic bacterium, designated K20C18050901T, was isolated from forest soil collected on 11 September 2017 from Dinghushan Biosphere Reserve, Guangdong Province, PR China (23° 10' 24'' N; 112° 32' 10'' E). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain K20C18050901T belongs to the genus Chitinophaga, and showed the highest similarities to Chitinophaga sancti NBRC 15057T (98.6 %) and Chitinophaga oryziterrae JCM 16595T (96.9 %). The major fatty acids (>10 %) were iso-C15 : 0, C16 : 1ω5c, summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c) and iso-C17 : 0 3-OH. The predominant respiratory quinone was menaquinone-7. The major polar lipid was phosphatidylethanolamine. The draft genome size of strain K20C18050901T was 8.36 Mb with a DNA G+C content of 44.7 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between strain K20C18050901T and C. sancti NBRC 15057T were 31.40 and 85.82 %, respectively. On the basis of phenotypic, genotypic and phylogenetic analysis, strain K20C18050901T represents a novel species of the genus Chitinophaga, for which the name Chitinophagasilvisoli sp. nov. is proposed. The type strain is K20C18050901T (=GDMCC 1.1411T=KCTC 62860T).

Azotobacter bryophylli sp. nov., isolated from the succulent plant Bryophyllum pinnatum.

A Gram-stain-negative, aerobic, nitrogen-fixing bacterium, designated strain L461T, was isolated from leaves of Bryophyllum pinnatum growing at the South China Agricultural University. Phylogenetic analysis of the 16S rRNA gene sequence indicated it as a member of the genus Azotobacter closely related to Azotobacter beijerinckii JCM 20725T (97.82 % similarity) and Azotobacter chroococcum ATCC 9043T (97.34 %). Its major fatty acid components were C16 : 1 ω9c and C16 : 0. Its predominant isoprenoid quinone was Q-9. Its major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, aminophospholipid, phospholipid and one unknown lipid. Its DNA G+C content was 64.9 mol% (Tm). DNA-DNA relatedness values between strain L461T and the reference strains of A. beijerinckii and A. chroococcum were 46.43 and 28.23 %, respectively. Biological and biochemical tests, protein patterns, genomic DNA fingerprinting, and comparison of cellular fatty acids distinguished strain L461T from the closely related Azotobacter species. Based on these data, the novel species Azotobacter bryophylli sp. nov. is proposed, with the type strain L461T (=KCTC 62195T=GDMCC 1.1250T).

Deminuibacter soli gen. nov., sp. nov., isolated from forest soil, and reclassification of Filimonas aurantiibacter as Arvibacter aurantiibacter comb. nov.

A novel strain, designated K23C18032701T, was isolated from a sample of forest soil collected from Dinghushan Biosphere Reserve, Guangdong Province, PR China. The strain was Gram-stain-negative, aerobic, motile and showed a shape change from a filamentous cell to coccobacilli. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the novel strain belongs to the family Chitinophagaceae, and showed the highest similarities to Arvibacter flaviflagrans JCM 31293T (95.0 %) and Filimonas aurantiibacter LMG 29039T (94.4 %). The major cellular fatty acids included iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The predominant polar lipid was phosphatidylethanolamine (PE). The predominant respiratory quinone was menaquinone-7. The major polyamine was sym-homospermidine. The draft genome size of strain K23C18032701T was 5.84 Mb with a DNA G+C content of 47.2 mol%. Based on phenotypic, genotypic and phylogenetic analysis, strain K23C18032701T represents a novel species of a new genus in the family Chitinophagaceae, for which the name Deminuibacter soli is proposed. The type strain is K23C18032701T (=GDMCC 1.1403T=KCTC 62913T). We also propose the reclassification of Filimonas aurantiibacter as Arvibacter aurantiibacter comb. nov. (type strain 1458T=NRRL B-65305T=LMG 29039T).

Mobility Aware Duty Cycling Algorithm (MADCAL) A Dynamic Communication Threshold for Mobile Sink in Wireless Sensor Network.

The hotspot issue in wireless sensor networks, with nodes nearest the sink node losing energy fastest and degrading network lifetime, is a well-referenced problem. Mobile sink nodes have been proposed as a solution to this. They do not completely remove the hotspot problem though, with nodes the sink passes most closely still expending more energy than others. This study proposes a lightweight algorithm, located in the media access control (MAC) layer of static nodes and utilising knowledge of predictable sink node mobility. This is in order to create a dynamic communication threshold between static nodes and the sink, within which static nodes awaken, lessening competition for sink communication between nodes. In utilising predictable mobility and factors already known to the static node, such as location and interference range, there is no need for energy-consuming messaging. Analysis and simulation results, tested on a lightweight implementation of a carrier-sense multiple-access-based MAC protocol, show a significant improvement in energy consumption in both controlled and random environments, with frame delivery improved to the point where sink speed is negated. This is when compared to the existing duty cycling approach.

A Quality of Service-Aware Secured Communication Scheme for Internet of Things-Based Networks.

The Internet of Things (IoT) is an emerging technology that aims to enable the interconnection of a large number of smart devices and heterogeneous networks. Ad hoc networks play an important role in the designing of IoT-enabled platforms due to their efficient, flexible, low-cost and dynamic infrastructures. These networks utilize the available resources efficiently to maintain the Quality of Service (QoS) in a multi-hop communication. However, in a multi-hop communication, the relay nodes can be malicious, thus requiring a secured and reliable data transmission. In this paper, we propose a QoS-aware secured communication scheme for IoT-based networks (QoS-IoT). In QoS-IoT, a Sybil attack detection mechanism is used for the identification of Sybil nodes and their forged identities in multi-hop communication. After Sybil nodes detection, an optimal contention window (CW) is selected for QoS provisioning, that is, to achieve per-flow fairness and efficient utilization of the available bandwidth. In a multi-hop communication, the medium access control (MAC) layer protocols do not perform well in terms of fairness and throughput, especially when the nodes generate a large amount of data. It is because the MAC layer has no capability of providing QoS to prioritized or forwarding flows. We evaluate the performance of QoS-IoT in terms of Sybil attack detection, fairness, throughput and buffer utilization. The simulation results show that the proposed scheme outperforms the existing schemes and significantly enhances the performance of the network with a large volume of data. Moreover, the proposed scheme is resilient against Sybil attack.

Rhizobium wuzhouense sp. nov., isolated from roots of Oryza officinalis.

Three bacterial isolates, designated W44T, W15 and W11, were isolated from the root of Oryza officinalis grown in Wuzhou, China. These isolates were Gram-negative, aerobic, motile and rod-shaped; demonstrated cellulase and urea activities; and formed cream-coloured colonies. The 16S rRNA gene sequence analysis indicated that the similarities between strain W44T and strains W15 and W11 were 100 %; all of them belonged to the genus Rhizobium and had the highest sequence similarity to Rhizobium rosettiformans W3T (98.7 %), followed by Rhizobium ipomoeae shin9-1T (98.2 %). Sequencing of housekeeping genes (recA, atpD, rpoB and glnA) of the novel isolates revealed similarities to members of established Rhizobium species to be less than 94.3 %. The values of DNA-DNA hybridization between strain W44T and the reference strains (R. rosettiformans W3T and R. ipomoeae shin9-1T) were 41.3 and 29.2 %, respectively. The major cellular fatty acid of strain W44T was summed feature 8 (C18 : 1ω9t and/or C18 : 1ω9c and/or C18 : 1ω7c). The polar lipid profile of strain W44T consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified lipids and two unidentified aminophospholipids. The G+C content of strain W44T was 62.4 mol%. In nodulation tests, none of the three strains could induce nodule formation in Glycine max, Phaseolus vulgaris or Medicago sativa. The nodulation gene (nodA), nitrogenase reductase gene (nifH) and virulence gene (virC) were not detected by PCR in these strains. Based on the above results and phenotypic features, a novel species, Rhizobium wuzhouense sp. nov., is proposed, with strain W44T (=CCTCC AB 2017179T=GDMCC 1.1257T=KCTC 62194T) as the type strain.

Paenibacillus bryophyllum sp. nov., a nitrogen-fixing species isolated from Bryophyllum pinnatum.

A nitrogen-fixing, endospore-forming bacterium, designated strain L201T was isolated from the leaves of Bryophyllum pinnatum growing in South China Agricultural University. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain L201T is affiliated with the genus Paenibacillus, and closely related to Paenibacillus albidus Q4-3T (97.4%), Paenibacillus odorifer DSM 15391T (97.3%) and Paenibacillus borealis DSM 13188T (97.2%). The main fatty acids components was anteiso-C15:0 (48.1%). The predominant isoprenoid quinone was MK-7. The major polar lipids were found to be diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The G+C content of strain L201T was 43.9%. DNA-DNA relatedness between L201T and the reference strain was 29.8%. Biological and biochemical tests, protein patterns, genomic DNA fingerprinting and comparison of cellular fatty acids distinguished strain L201T from the closely related Paenibacillus species. Based on these data, the novel species Paenibacillus bryophyllum sp. nov. is proposed, with the type strain L201T(= KCTC 33951 T = GDMCC 1.1251 T).

Construction of high-density genetic map and QTL mapping of yield-related and two quality traits in soybean RILs population by RAD-sequencing.

BACKGROUND: One of the overarching goals of soybean breeding is to develop lines that combine increased yield with improved quality characteristics. High-density-marker QTL mapping can serve as an effective strategy to identify novel genomic information to facilitate crop improvement. In this study, we genotyped a recombinant inbred line (RIL) population (Zhonghuang 24 × Huaxia 3) using a restriction-site associated DNA sequencing (RAD-seq) approach. A high-density soybean genetic map was constructed and used to identify several QTLs that were shown to influence six yield-related and two quality traits. RESULTS: A total of 47,472 single-nucleotide polymorphisms (SNPs) were detected for the RILs that were integrated into 2639 recombination bin units, with an average distance of 1.00 cM between adjacent markers. Forty seven QTLs for yield-related traits and 13 QTLs for grain quality traits were found to be distributed on 16 chromosomes in the 2 year studies. Among them, 18 QTLs were stable, and were identified in both analyses. Twenty six QTLs were identified for the first time, with a single QTL (qNN19a) in a 56 kb region explaining 32.56% of phenotypic variation, and an additional 10 of these were novel, stable QTLs. Moreover, 8 QTL hotpots on four different chromosomes were identified for the correlated traits. CONCLUSIONS: With RAD-sequencing, some novel QTLs and important QTL clusters for both yield-related and quality traits were identified based on a new, high-density bin linkage map. Three predicted genes were selected as candidates that likely have a direct or indirect influence on both yield and quality in soybean. Our findings will be helpful for understanding common genetic control mechanisms of co-localized traits and to select cultivars for further analysis to predictably modulate soybean yield and quality simultaneously.

Fine mapping of a Phytophthora-resistance gene RpsWY in soybean (Glycine max L.) by high-throughput genome-wide sequencing.

KEY MESSAGE: Using a combination of phenotypic screening, genetic and statistical analyses, and high-throughput genome-wide sequencing, we have finely mapped a dominant Phytophthora resistance gene in soybean cultivar Wayao. Phytophthora root rot (PRR) caused by Phytophthora sojae is one of the most important soil-borne diseases in many soybean-production regions in the world. Identification of resistant gene(s) and incorporating them into elite varieties are an effective way for breeding to prevent soybean from being harmed by this disease. Two soybean populations of 191 F2 individuals and 196 F7:8 recombinant inbred lines (RILs) were developed to map Rps gene by crossing a susceptible cultivar Huachun 2 with the resistant cultivar Wayao. Genetic analysis of the F2 population indicated that PRR resistance in Wayao was controlled by a single dominant gene, temporarily named RpsWY, which was mapped on chromosome 3. A high-density genetic linkage bin map was constructed using 3469 recombination bins of the RILs to explore the candidate genes by the high-throughput genome-wide sequencing. The results of genotypic analysis showed that the RpsWY gene was located in bin 401 between 4466230 and 4502773 bp on chromosome 3 through line 71 and 100 of the RILs. Four predicted genes (Glyma03g04350, Glyma03g04360, Glyma03g04370, and Glyma03g04380) were found at the narrowed region of 36.5 kb in bin 401. These results suggest that the high-throughput genome-wide resequencing is an effective method to fine map PRR candidate genes.

GmEXPB2, a Cell Wall ß-Expansin, Affects Soybean Nodulation through Modifying Root Architecture and Promoting Nodule Formation and Development.

Nodulation is an essential process for biological nitrogen (N2) fixation in legumes, but its regulation remains poorly understood. Here, a ß-expansin gene, GmEXPB2, was found to be critical for soybean (Glycine max) nodulation. GmEXPB2 was preferentially expressed at the early stage of nodule development. ß-Glucuronidase staining further showed that GmEXPB2 was mainly localized to the nodule vascular trace and nodule vascular bundles, as well as nodule cortical and parenchyma cells, suggesting that GmEXPB2 might be involved in cell wall modification and extension during nodule formation and development. Overexpression of GmEXPB2 dramatically modified soybean root architecture, increasing the size and number of cortical cells in the root meristematic and elongation zones and expanding root hair density and size of the root hair zone. Confocal microscopy with green fluorescent protein-labeled rhizobium USDA110 cells showed that the infection events were significantly enhanced in the GmEXPB2-overexpressing lines. Moreover, nodule primordium development was earlier in overexpressing lines compared with wild-type plants. Thereby, overexpression of GmEXPB2 in either transgenic soybean hairy roots or whole plants resulted in increased nodule number, nodule mass, and nitrogenase activity and thus elevated plant N and phosphorus content as well as biomass. In contrast, suppression of GmEXPB2 in soybean transgenic composite plants led to smaller infected cells and thus reduced number of big nodules, nodule mass, and nitrogenase activity, thereby inhibiting soybean growth. Taken together, we conclude that GmEXPB2 critically affects soybean nodulation through modifying root architecture and promoting nodule formation and development and subsequently impacts biological N2 fixation and growth of soybean.

[Isolation and Characterization of Microbes from Pericarpium Citri Reticulatae].

OBJECTIVE: The longer the Pericarpium Citri Reticulatae is preserved, the better medicinal values will be. The present work aims to isolate beneficial microbes isolated from the 7-year orange peel that might be used to produce high quality Pericarpium Citri Reticulatae. METHODS: The microbes isolated from the 7-year orange peel using 4 mediums were grouped by SDS-PAGE patterns of the whole-cell protein electrophoresis and IS-PCR DNA fingerprinting. The representative strains were further studied by physiological and biochemical tests, and phylogeny analysis. RESULTS: Total 23 bacteria were obtained from the 7-year orange peel. These strains were classified into 4 groups: the strains of group I belonged to Bacillus; the strains of group II, group III and group IV were closed to Paenibacillus. CONCLUSION: Among the representative strains of group I, II, III and IV, only the representative strain cp20 of group II has the ability of strong utilizing citrate obviously. The strain cp20 of group II were further applied to making Pericarpium Citri Reticulatae.

Barley farmland harbors a highly homogeneous soil bacterial community compared to wild ecosystems in the Qinghai-Xizang Plateau.

Introduction: Understanding patterns and processes of microbial biogeography in soils is important for monitoring ecological responses to human activities, particularly in ecologically vulnerable areas such as the Qinghai-Xizang Plateau. Highland barley is the staple food of local people and has mainly been cultivated along the Yarlung Zangbo River valley in Xizang. Methods: Here we investigated soil bacterial communities from 33 sampling sites of highland barley farmland in this region and compared them to those from wild ecosystems including alpine tundra, meadow, forest, and swamp. Additionally, the effects of environmental factors on bacterial communities, as well as the relative importance of stochastic and deterministic processes in shaping the beta diversity of soil bacterial communities in alpine ecosystems were assessed. Results: In contrast to soils of wild ecosystems, these farmland samples harbored a highly homogeneous bacterial community without significant correlations with geographic, elevation, and edaphic distances. Discriminant bacterial taxa identified for farmland samples belong to Acidobacteria, with Acidobacteria Gp4 as the dominant clade. Although Acidobacteria were the most abundant members in all ecosystems, characterized bacterial taxa of meadow and forest were members of other phyla such as Proteobacteria and Verrucomicrobia. pH and organic matter were major edaphic attributes shaping these observed patterns across ecosystems. Null model analyses revealed that the deterministic assembly was dominant in bacterial communities in highland barley farmland and tundra soils, whereas stochastic assembly also contributed a large fraction to the assembly of bacterial communities in forest, meadow and swamp soils. Discussion: These findings provide an insight into the consequences of human activities and agricultural intensification on taxonomic homogenization of soil bacterial communities in the Qinghai-Xizang Plateau.

Model-based exploration of the rationality of off-label use of cetirizine in Chinese pediatric patients: a prospective cohort study.

Aims: Cetirizine is frequently administered at an increased dosage in clinical practice and recommended by several guidelines. Nonetheless, the pharmacokinetic (PK) profile and real-world safety data remain insufficient in the Chinese pediatric population. The objective of the current study is to develop a population pharmacokinetic (PPK) model for cetirizine in Chinese pediatric patients and to investigate the rationale behind its off-label usage. Methods: A prospective cohort study was conducted, enrolling children who had been diagnosed with allergic diseases and prescribed cetirizine. The outcomes were safety and pharmacokinetic (PK) parameters. Cetirizine concentrations were measured using a pre-established analytical method. Subsequently, a PK model was developed, followed by model evaluation and simulation. The developed PK model was employed to investigate the drug exposure differences across various age groups and to simulate scenarios of potential overdose. Results: Sixty-three children were enrolled, and 24 of them received a cetirizine dose exceeding the recommended dosage. A PPK model, based on published literature, served as the basis of our analysis, with adjustment made to estimate certain parameters. The final model evaluation and validation indicated accurate predictive performance and robust parameter estimation. Simulations conducted for the label-dose among age 1-12 indicated median maximum concentration at steady state (Cmax,ss) of 7 year old children could be the highest. The model was also used to predict the off-label dose scenarios and overdose patient to support the clinical decision. There were no adverse drug reactions in either group. Conclusion: This study provides evidence-based and model-based exploration for optimizing cetirizine usage in Chinese pediatric patients. The cetirizine PPK model showed accurate predictive performance and could be utilized to simulate individual patient exposure in real-world clinical scenarios.

Endophyte-mediated enhancement of salt resistance in Arachis hypogaea L. by regulation of osmotic stress and plant defense-related genes.

Introduction: Soil salinization poses a significant environmental challenge affecting plant growth and agricultural sustainability. This study explores the potential of salt-tolerant endophytes to mitigate the adverse effects of soil salinization, emphasizing their impact on the development and resistance of Arachis hypogaea L. (peanuts). Methods: The diversity of culturable plant endophytic bacteria associated with Miscanthus lutarioriparius was investigated. The study focused on the effects of Bacillus tequilensis, Staphylococcus epidermidis, and Bacillus siamensis on the development and germination of A. hypogaea seeds in pots subjected to high NaCl concentrations (200 mM L-1). Results: Under elevated NaCl concentrations, the inoculation of endophytes significantly (p < 0.05) enhanced seedling germination and increased the activities of enzymes such as Superoxide dismutase, catalase, and polyphenol oxidase, while reducing malondialdehyde and peroxidase levels. Additionally, endophyte inoculation resulted in increased root surface area, plant height, biomass contents, and leaf surface area of peanuts under NaCl stress. Transcriptome data revealed an augmented defense and resistance response induced by the applied endophyte (B. tequilensis, S. epidermidis, and B. siamensis) strain, including upregulation of abiotic stress related mechanisms such as fat metabolism, hormones, and glycosyl inositol phosphorylceramide (Na+ receptor). Na+ receptor under salt stress gate Ca2+ influx channels in plants. Notably, the synthesis of secondary metabolites, especially genes related to terpene and phenylpropanoid pathways, was highly regulated. Conclusion: The inoculated endophytes played a possible role in enhancing salt tolerance in peanuts. Future investigations should explore protein-protein interactions between plants and endophytes to unravel the mechanisms underlying endophyte-mediated salt resistance in plants.

Population Pharmacokinetics of Cabozantinib in Metastatic Renal Cell Carcinoma Patients: Towards Drug Expenses Saving Regimens.

INTRODUCTION: Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on average by 57%. Combined with the long terminal half-life of cabozantinib (99 h), this creates possibilities to extend the dosing interval to reduce drug expenses whilst maintaining equivalent exposure. OBJECTIVES: The primary objective was to evaluate the population pharmacokinetic (POPPK) model of cabozantinib developed for its registration using real-world patients' therapeutic drug monitoring (TDM) data. The secondary objective was to design, simulate, and evaluate alternative dose regimens with the aim to reduce drug expenses whilst maintaining comparable exposure. METHODS: Retrospective TDM data from mRCC patients treated with cabozantinib were obtained. The data were evaluated using the published Food and Drug Administration (FDA) cabozantinib POPPK model, a two-compartment disposition model with a dual (fast and slow) lagged first-order absorption process derived from FDA registration documents, as a basis. Subsequently, simulations of alternative drug expenses saving regimens were evaluated. RESULTS: Twenty-seven mRCC patients with 75 pharmacokinetic observations were included. Patients were treated for a median of 75 days with a median dose of 40 mg. Model evaluation results showed that the cabozantinib TDM concentrations were adequately predicted by the published FDA cabozantinib POPPK model, except for a slightly higher clearance (CL) of 3.11 L/h compared to the reported value (2.23 L/h). The simulation study indicated that an alternative dose regimen that consists of taking 60 mg of cabozantinib for 2 days and then skipping 1 day results in comparable average exposure when compared with a 40 mg daily dose, both without food interaction, while saving 33.3% of the total drug expenses per month. The food effect of a high-fat meal was also taken into account when simulating other alternative dose regimens; 40 mg every 72 h combined with a high-fat meal resulted in comparable exposure when compared with a 20 mg daily dose fasted, while saving 66.7% in drug expenses. CONCLUSIONS: In this study, the optimized cabozantinib POPPK model resulted in adequate prediction of real-world cabozantinib pharmacokinetic data. Alternative dosing regimens with and without using known food interactions were proposed that resulted in potential strategies to significantly reduce cabozantinib drug expenses.