PD-1 and LAG-3-positive T cells are associated with clinical outcomes of relapsed/refractory multiple myeloma patients.

OBJECTIVE: To investigate the frequency of PD-1 and LAG-3-positive T cells in relapsed/refractory multiple myeloma (RRMM) patients and its clinical significance. METHODS: This prospective observational study enrolled a total of 71 RRMM patients, as well as 70 MM patients (non-refractory) and 70 healthy individuals during January 2018 to March 2021. The frequency of circulating CD4+ and CD8+ T cells expressing PD-1 and LAG-3 was analyzed using flow cytometry. Serum cytokines of IL-6, IL-17, CRP, TNF-α and TGF-ß were evaluated by enzyme linked immunosorbent assay (ELISA). RESULTS: Significant higher 1-year mortality rate was found in RRMM patients compared with the MM patients. In both CD4+ and CD8+ T cells, the frequencies of PD-1+, LAG-3+ and PD-1+/LAG-3+ T cells were markedly higher in the RRMM patients and the deceased patients, compared with the MM patients and the survival patients, respectively. All cytokines were remarkably higher in RRMM and MM patients than in the healthy control, while only serum levels of IL-6 and IL-17 were markedly higher in RRMM patients compared with the MM patients. Positive correlation was observed among the IL-6, IL-17 and the frequencies of circulating T cells in both CD4+ and CD8+ T cells in RRMM and MM patients. The frequency of CD8+PD-1+LAG-3+ T cells showed the best sensitivity 82.61% and specificity 76.06% for diagnosis of RRMM using ROC curve. Meanwhile, the frequency of CD4+PD-1+ cells showed the best sensitivity 84.00% and specificity 97.35% for prediction of patients' mortality by ROC curve. The frequencies of CD4+PD-1+, CD8+PD-1+/LAG-3+, as well as IL-6, IL-17 and TNF-α were found as risk factors for incidence of RRMM in all MM patients. CONCLUSION: The frequency of PD-1 and LAG-3-positive T cells is associated with the clinical severity and inflammation in RRMM patients, which may also serve as potential biomarkers for its diagnosis.

High Discharge Capacity and Ultra-Fast-Charging Sodium Dual-Ion Battery Based on Insoluble Organic Polymer Anode and Concentrated Electrolyte.

Sodium-based dual-ion batteries have shown great promise for large-scale energy storage applications due to their wide operating voltages, environmental friendliness, abundant sodium resources, and low cost, which are widely investigated by researchers. However, the development of high-performance anode materials is a key requirement for the realization of such electrochemical energy storage systems at the practical application level. Carbonaceous anode materials based on intercalation/deintercalation mechanisms typically exhibit low discharge capacities, while metal-based materials based on conversion or alloying reactions show unsatisfactory stability in performance. On the contrary, organic materials display high theoretical capacities due to their flexible molecular structure designability and stable cyclic performance with fast reaction kinetics based on the unique enolization reaction. Herein, we report an organic polymer anode material of polyimide (PNTO), combined with a high-concentration electrolyte; the sodium-based dual-ion battery system constructed exhibits outstanding electrochemical performance. The full battery shows an ultra-high specific discharge capacity of 293.2 mAh g-1 and can be cycled stably for 3200/5600/4100 cycles at ultra-high rates of 60/120/150 C without degradation. Furthermore, the dual-ion battery system demonstrates an extremely low self-discharge rate of 0.03% h-1 and superior fast-charging-slow-discharging performance. It is one of the best performances reported up to now for a dual-ion full battery based on an organic polymer anode. This novel battery system design strategy will facilitate the advancement of high-performance organic-based dual-ion batteries and is expected to be a promising candidate for large-scale energy storage applications.

Comparative transcriptomic analysis of two Cucumis melo var. saccharinus germplasms differing in fruit physical and chemical characteristics.

BACKGROUND: Hami melon (Cucumis melo var. saccharinus) is a popular fruit in China because of its excellent taste, which is largely determined by its physicochemical characteristics, including flesh texture, sugar content, aroma, and nutrient composition. However, the mechanisms by which these characteristics are regulated have not yet been determined. In this study, we monitored changes in the fruits of two germplasms that differed in physicochemical characteristics throughout the fruit development period. RESULTS: Ripe fruit of the bred variety 'Guimi' had significantly higher soluble sugar contents than the fruit of the common variety 'Yaolong.' Additionally, differences in fruit shape and color between these two germplasms were observed during development. Comparative transcriptome analysis, conducted to identify regulators and pathways underlying the observed differences at corresponding stages of development, revealed a higher number of differentially expressed genes (DEGs) in Guimi than in Yaolong. Moreover, most DEGs detected during early fruit development in Guimi were associated with cell wall biogenesis. Temporal analysis of the identified DEGs revealed similar trends in the enrichment of downregulated genes in both germplasms, although there were differences in the enrichment trends of upregulated genes. Further analyses revealed trends in differential changes in multiple genes involved in cell wall biogenesis and sugar metabolism during fruit ripening. CONCLUSIONS: We identified several genes associated with the ripening of Hami melons, which will provide novel insights into the molecular mechanisms underlying the development of fruit characteristics in these melons.

TYMSOS drives the proliferation, migration, and invasion of gastric cancer cells by regulating ZNF703 via sponging miR-4739.

Gastric cancer (GC) is a kind of malignancy originating from the epithelium of gastric mucosa. Long noncoding RNAs (lncRNAs) are tightly related to the GC progression. Herein, our research was meant to investigate a novel lncRNA thymidylate synthetase opposite strand (TYMSOS) in GC. Quantitative real-time polymerase chain reaction was used to analyze TYMSOS expression in GC cells. 5-Ethynyl-2'-deoxyuridine, flow cytometry analysis, and transwell assay detected the influence of TYMSOS on GC cell proliferation, apoptosis, migration, and invasion. Subcellular fractionation and fluorescent in situ hybridization assays determined the cellular localization of TYMSOS in GC cells. Bioinformatics programs, RNA-binding protein immunoprecipitation, RNA pull-down, and luciferase reporter assays measured the molecular interplays of TYMSOS in GC cells. In brief, TYMSOS was highly expressed in GC cells, and TYMSOS silence inhibited GC cell proliferation, migration, and invasion while elevating cell apoptosis. Functionally, TYMSOS functioned as a competing endogenous RNA to posttranscriptionally modulate GC progression. TYMSOS interacted with miR-4739 to regulate its target gene zinc finger protein 703. Collectively, our study proved the tumor-promoting role of TYMSOS in GC cells, which might offer the utility value for GC treatment.

The Clinical Significance of Abnormal Tim-3 Expression on NK Cells from Patients with Gastric Cancer.

AIM: To investigate the clinical significance of Tim-3 (T-cell immunoglobulin- and mucin-domain-containing molecule 3) expression in natural killer (NK) cells from patients with gastric cancer. MATERIALS AND METHODS: Sixty-two patients with gastric cancer and 32 healthy controls were recruited for this study. Tim-3 expression in peripheral blood samples was analyzed using flow cytometry. The expression pattern of Tim-3 on NK cells was also confirmed using a gastric cancer-bearing mouse model. To further investigate the mechanisms that regulate Tim-3 expression, T-bet(-/-), Eomes(-/-), and Eomes/T-bet double knockout mice were utilized. Additionally, we statistically analyzed the clinical significance of Tim-3 expression on NK cells. RESULTS: We found that the levels of Tim-3 in NK cells obtained from patients with gastric cancer were significantly higher than the levels in healthy controls. Clinical analyses showed that Tim-3 levels on NK cells were associated with advanced tumor stage. In a tumor-bearing mouse model, Tim-3 levels in NK cells increased with tumor growth, indicating that tumor progression could induce Tim-3 expression in NK cells. Finally, we report that T-bet is a key factor involved in regulating Tim-3 expression. CONCLUSION: Our data indicate that Tim-3 expression on NK cells is regulated by T-bet, and that Tim-3 levels correlate with advanced stages of gastric cancer.

[Functional study of transcription factor Hlx modified dendritic cell line DC2.4].

AIM: To transfect Hlx into mouse dendritic cell line DC2.4 and observe the effect of hlx on function of dendritic cells. METHODS: The eukaryotic expression vector PIRES2-EGFP/Hlx was transfected into DC2.4 by liposomes. The transfection efficiency was identified through FACS. RT-PCR and Real-time PCR were used to test the transcription level of Hlx in DC2.4. Forty-eight hours after transfection, DC2.4 cells were studied for cytokine production, cell phenotype, phagocytosis, unilateral mixed lymphocyte reaction. RESULTS: The pIRES2-EGFP/Hlx vector was transfected into DC2.4 with the transfection efficiency of up to 60%. Highly expressed Hlx in DC2.4 increased the expression of maturation makers including CD80 and CD86, and major histocompatibility complex-II. Functional assay showed that over-expression of Hlx in DC2.4 increased the interleukin-12 transcription and decreased DC endocytosis. The Hlx modified DC2.4 highly expressed IL-10 and TGF-ß at the same time. Furthermore, it was shown that in a unilateral mixed lymphocyte reaction model, Hlx modified DC2.4 inhibited proliferation of lymphocytes. CONCLUSION: Transient over-expression of Hlx in DC2.4 promotes DC2.4 maturation and up-regulates IL-12, IL-10 and TGF-ß expression. However, the Hlx modified DC2.4 cells functionally appear as regulatory dendritic cells.