Circulating tumor DNA determining hyperprogressive disease after CAR-T therapy alarms in DLBCL: a case report and literature review

Chimeric antigen receptor T-cell therapy (CAR-T) has been widely applied in the clinical practice of relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) due to its promising effects. Hyperprogressive disease (HPD) has gained attention for rapid tumor progression and has become a therapeutic and prognostic challenge. Here, we present a patient who had suffered from several recurrences previously and controlled well with a very small tumor lesion left was infused with CD19/CD22 bispecific CAR-T, with no immune effector cell-associated neurotoxicity syndrome, or cytokine release syndrome observed. However, rapid deterioration, subsequent imaging examination, circulating tumor DNA, and serum biomarkers detection identified HPD. The patient did not respond to salvage treatment and died 40 days after infusion. To our knowledge, only one case of HPD in DLBCL after CAR-T therapy has been reported. This fatal case alarmed the risk of HPD and the ctDNA profile monitoring we used was performed as a non-invasive method to diagnose HPD, providing far-reaching practical instruction for CAR-T therapy

MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK

Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues (p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis (p < 0.05) and good prognosis (p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro. miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC

Transcriptomic profiling revealed important roles of amino acid metabolism in fruiting body formation at different ripening times in Hypsizygus marmoreus

IntroductionHypsizygus marmoreus is an industrial mushroom that is widely cultivated in East Asia. Its long postripening stage before fruiting severely limits its industrialized production.MethodsFive different mycelial ripening times (30, 50, 70, 90, and 100 d) were chosen and primordia (30P, 50P, 70P, 90P, and 110P) were collected for comparative transcriptomic analyses. The corresponding substrates (30F, 50F, 70F, 90F, and 110F) were used for nutrient content and enzyme activity determination.ResultsIn pairwise comparisons between 110P and other primordia, a total of 1,194, 977, 773, and 697 differentially expressed genes (DEGs) were identified in 30P_110P, 50P_110P, 70P_110P, and 90P_110P, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) functional enrichment analyses revealed that the DEGs were mainly associated with amino acid metabolism, and lipid and carbohydrate metabolism pathways. Tyrosine, tryptophan, phenylalanine and histidine metabolism were enriched in all groups. Among the main carbon nutrients, the contents of cellulose and hemicellulose were high, and the lignin content decreased with the extension of the ripening time. Laccase had the highest activity, and acid protease activity decreased with the extension of the ripening time.DiscussionThe highly enrichment for amino acid metabolic pathways in primordia reveals that these pathways are essential for fruiting body formation in H. marmoreus, and these results will provide a basis for the optimization of its cultivation

Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs

MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA–target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis

Nitrogen-Doped Porous MXene (Ti3C2) for Flexible Supercapacitors with Enhanced Storage Performance

Flexible supercapacitors (FSCs) are limited in flexible electronics applications due to their low energy density. Therefore, developing electrode materials with high energy density, high electrochemical activity, and remarkable flexibility is challenging. Herein, we designed nitrogen-doped porous MXene (N-MXene), using melamine-formaldehyde (MF) microspheres as a template and nitrogen source. We combined it with an electrospinning process to produce a highly flexible nitrogen-doped porous MXene nanofiber (N-MXene-F) as a self-supporting electrode material and assembled it into a symmetrical supercapacitor (SSC). On the one hand, the interconnected mesh structure allows the electrolyte to penetrate the porous network to fully infiltrate the material surface, shortening the ion transport channels; on the other hand, the uniform nitrogen doping enhances the pseudocapacitive performance. As a result, the as-assembled SSC exhibited excellent electrochemical performance and excellent long-term durability, achieving an energy density of 12.78 Wh kg−1 at a power density of 1080 W kg−1, with long-term cycling stability up to 5000 cycles. This work demonstrates the impact of structural design and atomic doping on the electrochemical performance of MXene and opens up an exciting possibility for the fabrication of highly FSCs

Effects of temperature-related changes on charred bone in soil: From P release to microbial community

Phosphorus (P) is one of the most common limited nutrients in terrestrial ecosystems. Animal bones, with abundant bioapatite, are considerable P sources in terrestrial ecosystems. Heating significantly promotes P release from bone bioapatite, which may alleviate P limitation in soil. This study aimed to explore P release from charred bone (CB) under heating at various temperatures (based on common natural heating). It showed that heating at ∼300 °C significantly increased the P release (up to ∼30 mg/kg) from CB compared with other heating temperatures. Then, the subsequent changes of available P and pH induced evident alternation of soil microbial community composition. For instance, CB heated at ∼300 °C caused elevation of phosphate-solubilizing fungi (PSF) abundance. This further stimulated P mobility in the soil. Meanwhile, the fungal community assembly process was shifted from stochastic to deterministic, whereas the bacterial community was relatively stable. This indicated that the bacterial community showed fewer sensitive responses to the CB addition. This study hence elucidated the significant contribution of heated bone materials on P supply. Moreover, functional fungi might assist CB treated by natural heating (e.g., fire) to construct P “Hot Spots”

Engineered magnetosomes fused to functional molecule (protein A) provide a highly effective alternative to commercial immunomagnetic beads

Abstract Background Magnetosomes (also called bacterial magnetic nanoparticles; BMPs) are biomembrane-coated nanoparticles synthesized by magnetotactic bacteria (MTB). Engineered BMPs fused to protein A (termed ∆F-BMP-FA) bind antibodies (Abs) automatically, and thus provide a series of potential advantages. However, no report so far has systematically evaluated functional applicability of genetically engineered BMPs. Results We evaluated properties of ∆F-BMP-FA, and developed/optimized culture methods for host strain Magnetospirillum gryphiswaldense ΔF-FA, ∆F-BMP-FA extraction conditions, conditions for Ab conjugation to ∆F-BMP-FA surface, and procedures for antigen detection using ∆F-BMP-FA/Ab complexes (termed BMP-A-Ab). Fed-batch culture for 36 h in a 42-L fermentor resulted in yields (dry weight) of 2.26 g/L for strain ΔF-FA and 62 mg/L for ∆F-BMP-FA. Optimal wash cycle number for ∆F-BMP-FA purification was seven, with magnetic separation following each ultrasonication step. Fusion of protein A to BMPs resulted in ordered arrangement of Abs on BMP surface. Linkage rate 962 μg Ab per mg ∆F-BMP-FA was achieved. BMP-A-Ab were tested for detection of pathogen (Vibrio parahaemolyticus; Vp) surface antigen and hapten (gentamicin sulfate). Maximal Vp capture rate for BMP-A-Ab was 90% (higher than rate for commercial immunomagnetic beads), and detection sensitivity was 5 CFU/mL. ∆F-BMP-FA also bound Abs from crude mouse ascites to form complex. Lowest gentamicin sulfate detection line for BMP-A-Ab was 0.01 ng/mL, 400-fold lower than that for double Ab sandwich ELISA, and gentamicin sulfate recovery rate for BMP-A-Ab was 93.2%. Conclusion Our findings indicate that engineered BMPs such as ∆F-BMP-FA are inexpensive, eco-friendly alternatives to commercial immunomagnetic beads for detection or diagnostic immunoassays, and have high Ab-conjugation and antigen-adsorption capacity

Shufeng Jiedu capsules for treating acute exacerbations of chronic obstructive pulmonary disease: a systematic review and meta-analysis

Background: Chinese herbal medicine is widely used in combination with usual care for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in China. Shufeng Jiedu capsule (SFJD) is a Chinese patent medicine. The effectiveness and safety of SFJD for AECOPD remains uncertain.Methods: A systematic review of randomized control trials was performed. We included trials in patients diagnosed with AECOPD, who received SFJD as a single intervention or in combination with usual treatment. PubMed, Cochrane Library, EMBASE, CINAHL and four Chinese databases were searched from inception to April 2019. Two reviewers independently screened studies, extracted study data and assessed risk of bias. Meta-analysis was performed using RevMan 5.3 software. We performed subgroup analyses and sensitivity analyses according to the predefined protocol. Quality of evidence was assessed using GRADE.Results: 13 RCTs (1,036 patients, of which 936 were inpatients) were included. The mean age ranged from 52 to 67 and approximately 60% of patients were male. These RCTs had a high risk of bias due to lack of blinding and other factors. SFJD combined with usual care (including antimicrobials) compared to usual care alone was associated with a significant reduction in treatment failure, from 20.1% to 8.3% (11 trials; 815 patients; relative risk 0.43, 95% confidence interval [CI] 0.30 to 0.62) and duration of hospital admission (2 trials; 79 patients; mean difference -4.35 days, 95% CI -5.28 to -3.43 days; low certainty ). Low or very low certainty evidence suggested benefit from SFJD compared to controls in terms of PaCO2, PaO2, FEV1/FVC ratio, clinical symptoms, white cell counts, inflammatory markers and health related quality of life. No significant difference in adverse events was found in a pooled analysis. Conclusion: For hospitalized adults with AECOPD, SFJD may reduce treatment failure, shorten hospital stay, and improve symptoms and signs. However, the quality of the evidence is very low to low due to the potential risk of bias and inconsistency among included trials. Further large, high quality RCTs are needed