A novel prognostic classification integrating lipid metabolism and immune co-related genes in acute myeloid leukemia.

Background: As a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML. Methods: First, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored. Results: Eight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs. Conclusions: This study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report.

The effectiveness of the tyrosine kinase inhibitor ALK (TKI) for non-small cell lung cancer has been confirmed. However, resistance to ALK-TKIs seems inevitable. Mutations in the ALK kinase domain have been reported as an important mechanism of acquired resistance to ALK therapy. However, patients with de novo ALK kinase domain mutations and ALK rearrangements who were not treated with ALK inhibitors have rarely been reported. Here, we report a case of primary drug resistance to first- and second-generation ALK inhibitors in a NSCLC patient with ALK-rearrangement. The next-generation sequencing test of the pathological biopsy showed that the de novo ALK kinase domain mutation F1174L-cis-S1189C may be the cause of primary drug resistance.

The protective effect of rutin against lipopolysaccharide induced acute lung injury in mice based on the pharmacokinetic and pharmacodynamic combination model.

Rutin is a flavonoid compound with many pharmacological activities, including antioxidation, anti-inflammation and cardiovascular and cerebrovascular protection. However, there are great limitations in clinical application in view of its poor solubility and slow absorption in vivo. In this study, a pharmacokinetic and pharmacodynomic model was adopted to study the correlation of the pharmacokinetics and pharmacodynomics of rutin in lipopolysaccharide-induced acute lung injury mice. Rutin was intragastrically administered continuously for 5 days at a dose of 200 mg/kg/d, and pharmacokinetic and pharmacodynamic indicators were measured every day after administration, including the blood concentration of rutin, the W/D ratio of lungs, the nitric oxide content and the expression levels of TLR4, TRAF6, IκB and P-IκB proteins. The results indicated that rutin can exert an anti-inflammatory protective effect by improving lung tissue injury, significantly decreasing the synthesis of the inflammatory mediator nitric oxide, and inhibiting the protein expression levels of TLR4, TRAF6 and P-IκB. The absorption of rutin conformed to a one-compartment model with the pharmacokinetic parameters as follows: t1/2α= 9.76 h, t1/2ß= 19.44 h, Tmax= 24.00 h, Cmax= 22.65 µg/ml and AUC(0-t)= 518.58 µg/ml·h. A PK-PD combination model was established to fit the optimal administration time of rutin with a one-compartment-Sigmod Emax model connected to the effect site. Meanwhile,the PK-PD combination model was a better approach for evaluating the relationships between the five pharmacodynamic indicators and the pharmacokinetic characteristics of rutin. The correlation between the pharmacokinetics and pharmacodynamics of rutin was quantitatively analysed to provide a theoretical basis for the research and development of new anti-inflammatory drugs in clinical practice.

TatD DNases Contribute to Biofilm Formation and Virulence in Trueperella pyogenes.

TatD DNases are conserved proteins in a variety of organisms and are considered potential virulence factors in Plasmodium falciparum and Streptococcus pneumoniae. However, the function of TatD DNases has not yet been determined in Trueperella pyogenes, which causes various infections in animals and leads to economic losses. In this study, we describe the roles of TatD DNases in T. pyogenes (TpTatDs). A bioinformatics analysis was performed to investigate the sequence characteristics of TpTatDs, and then the ability of recombinant TatD proteins to hydrolyze DNA was determined in the presence of divalent cations. Moreover, we constructed tatD-deficient mutants. The biofilms formed by the wild-type and mutant strains were observed under a microscope. The mortality and bacterial load in the spleen of mice infected with the wild-type strain and tatD-deficient mutants were determined to obtain insights into the role of TatDs in the virulence of T. pyogenes. Two TatD DNases were identified in T. pyogenes. They were Mg2+-dependent DNases and exhibited DNA endonuclease activity. Compared with those formed by the parental strain, biofilms formed by mutants showed a significantly reduced thickness and biomass. Moreover, mutants produced a lower bacterial load in the spleen of mice and compromised virulence. Our data indicated that TatD DNases in T. pyogenes are involved in biofilm formation and required for virulence during infections.

Favorable Marker Alleles for Panicle Exsertion Length in Rice (Oryza sativa L.) Mined by Association Mapping and the RSTEP-LRT Method.

The panicle exsertion length (PEL) in rice (Oryza sativa L.) is an important trait for hybrid seed production. We investigated the PEL in a chromosome segment substitution line (CSSL) population consisting of 66 lines and a natural population composed of 540 varieties. In the CSSL population, a total of seven QTLs for PEL were detected across two environments. The percentage of phenotypic variance explained (PVE) ranged from 10.22 to 50.18%, and the additive effect ranged from -1.77 to 6.47 cm. Among the seven QTLs, qPEL10.2 had the largest PVE, 44.05 and 50.18%, with an additive effect of 5.91 and 6.47 cm in 2015 and in 2016, respectively. In the natural population, 13 SSR marker loci were detected that were associated with PEL in all four environments, with the PVE ranging from 1.20 to 6.26%. Among the 13 loci, 7 were novel. The RM5746-170 bp allele had the largest phenotypic effect (5.11 cm), and the typical carrier variety was Qiaobinghuang. An RM5620-RM6100 region harboring the EUI2 locus on chromosome 10 was detected in both populations. The sequencing results showed that the accessions with a shorter PEL contained the A base, while the accessions with a longer PEL contained the G base at the 1,475 bp location of the EUI2 gene.

QTL Detection and Elite Alleles Mining for Stigma Traits in Oryza sativa by Association Mapping.

Stigma traits are very important for hybrid seed production in Oryza sativa, which is a self-pollinated crop; however, the genetic mechanism controlling the traits is poorly understood. In this study, we investigated the phenotypic data of 227 accessions across 2 years and assessed their genotypic variation with 249 simple sequence repeat (SSR) markers. By combining phenotypic and genotypic data, a genome-wide association (GWA) map was generated. Large phenotypic variations in stigma length (STL), stigma brush-shaped part length (SBPL) and stigma non-brush-shaped part length (SNBPL) were found. Significant positive correlations were identified among stigma traits. In total, 2072 alleles were detected among 227 accessions, with an average of 8.3 alleles per SSR locus. GWA mapping detected 6 quantitative trait loci (QTLs) for the STL, 2 QTLs for the SBPL and 7 QTLs for the SNBPL. Eleven, 5, and 12 elite alleles were found for the STL, SBPL, and SNBPL, respectively. Optimal cross designs were predicted for improving the target traits. The detected genetic variation in stigma traits and QTLs provides helpful information for cloning candidate STL genes and breeding rice cultivars with longer STLs in the future.

Identification of a Candidate Gene for Panicle Length in Rice (Oryza sativa L.) Via Association and Linkage Analysis.

Panicle length (PL) is an important trait for improving panicle architecture and grain yield in rice (Oryza sativa L.). Three populations were used to identify QTLs and candidate genes associated with PL. Four QTLs for PL were detected on chromosomes 4, 6, and 9 through linkage mapping in the recombinant inbred line population derived from a cross between the cultivars Xiushui79 (short panicle) and C-bao (long panicle). Ten SSR markers associated with PL were detected on chromosomes 2, 3, 5, 6, 8, 9, and 10 in the natural population consisting of 540 accessions collected from East and Southeast Asia. A major locus on chromosome 9 with the largest effect was identified via both linkage and association mapping. LONG PANICLE 1 (LP1) locus was delimited to a 90-kb region of the long arm of chromosome 9 through fine mapping using a single segment segregating F2 population. Two single nucleotide polymorphisms (SNPs) leading to amino acid changes were detected in the third and fifth exons of LP1. LP1 encodes a Remorin_C-containing protein of unknown function with homologs in a variety of species. Sequencing analysis of LP1 in two parents and 103 rice accessions indicated that SNP1 is associated with panicle length. The LP1 allele of Xiushui79 leads to reduced panicle length, whereas the allele of C-bao relieves the suppression of panicle length. LP1 and the elite alleles can be used to improve panicle length in rice.