[Levels and Clinical Significances of sPD-1 and sPD-L1 in Peripheral Blood of Lymphoma Patients].

OBJECTIVE: To observe the levels of soluble programmed cell death protein 1 (sPD-1) and soluble programmed cell death ligand 1 (sPD-L1) in peripheral blood of lymphoma patients, and reveal their clinical significances. METHODS: The peripheral blood specimens and clinical data of 64 newly diagnosed lymphoma patients and 30 healthy volunteers were collected. The levels of sPD-1 and sPD-L1 were detected by enzyme-linked immunosorbent assay (ELISA), and their correlations with clinical characteristics of the patients including pathological type, stage, lactate dehydrogenase (LDH) level, T cell subsets were analyzed. RESULTS: The levels of both sPD-1 and sPD-L1 in peripheral blood of lymphoma patients were higher than those of normal controls (P <0.05). There were no significant differences in sPD-1 and sPD-L1 levels in peripheral blood between Hodgkin lymphoma and non-Hodgkin lymphoma patients. Different pathological subtypes of lymphoma had different levels of sPD-1. The level of sPD-1 in patients with T-cell lymphoma was higher than that in patients with B-cell lymphoma (P =0.001). The levels of both sPD-1 and sPD-L1 in patients with Ann Arbor stage III and IV were higher than those in patients with stage I and II (P <0.05). The level of sPD-L1 in patients with abnormally increased LDH was higher than that in patients with normal LDH (P =0.001), but there was no significant difference in sPD-1 level. T cell subset analysis showed that the level of sPD-L1 was negatively correlated to CD4+ T cell content (r =-0.265). CONCLUSION: The levels of sPD-1 and sPD-L1 in peripheral blood of lymphoma patients are related to the pathological type, Ann Arbor stage, LDH content and T cell subsets, and will be potential biomarkers in predicting the prognosis of lymphoma.

H2O2 and Phosphorylated Peptide Dual-Responsive Nanochannel Device.

Oxidation and protein phosphorylation are critical mechanisms involved in regulating various cellular activities. Increasing research has suggested that oxidative stress could affect the activities of specific kinases or phosphatases, leading to alterations in the phosphorylation status of certain proteins. Ultimately, these alterations can affect cellular signaling pathways and gene expression patterns. However, the relationship between oxidation and protein phosphorylation remains complex and not yet fully understood. Therefore, the development of effective sensors capable of detecting both oxidation and protein phosphorylation simultaneously presents an ongoing challenge. To address this need, we introduce a proof-of-concept nanochannel device that is dual-responsive to both H2O2 and phosphorylated peptide (PP). Specifically, we design a peptide GGGCEG(GPGGA)4CEGRRRR, which contains an H2O2-sensitive unit CEG, an elastic peptide fragment (GPGGA)4, and a phosphorylation site recognition fragment RRRR. When the peptides are immobilized on the inner walls of conical nanochannels in a polyethylene terephthalate membrane, this peptide-modified nanochannel device exhibits a sensitive response to both H2O2 and PPs. The peptide chains undergo a random coil-to-α-helix transition in response to H2O2, which leads to a close-to-open transition of the nanochannel, accompanied with a remarkable increase in the transmembrane ionic current. In contrast, binding of the peptides with PPs shields the positive charge of the RRRR fragments, causing a decrease of the transmembrane ionic current. These unique features enable the sensitive detection of reactive oxygen species released by 3T3-L1 cells stimulated by platelet-derived growth factor (PDGF) as well as PDGF-induced change in the PP level. Real-time kinase activity monitoring further confirms the device's potential utility for kinase inhibitor screening.

Comprehensive analysis of the FOXA1-related ceRNA network and identification of the MAGI2-AS3/DUSP2 axis as a prognostic biomarker in prostate cancer.

Background: Prostate cancer (PCa) is the second most common cause of cancer-related deaths in American men. Even though increasing evidence has disclosed the competitive endogenous RNA (ceRNA) regulatory networks among cancers, the complexity and behavior characteristics of the ceRNA network in PCa remain unclear. Our study aimed to investigate the forkhead box A1 (FOXA1)-related ceRNA regulatory network and ascertain potential prognostic markers associated with PCa. Methods: RNA sequence profiles downloaded from The Cancer Genome Atlas (TCGA) were analyzed to recognize differentially expressed genes (DEGs) derived from tumor and non-tumor adjacent samples as well as FOXA1low and FOXA1high tumor samples. The enrichment analysis was conducted for the dysregulated mRNAs. The network for the differentially expressed long non-coding RNA (lncRNA)-associated ceRNAs was then established. Survival analysis and univariate Cox regression analysis were executed to determine independent prognostic RNAs associated with PCa. The correlation between DUSP2 and immune cell infiltration level was analyzed. Tissue and blood samples were collected to verify our network. Molecular experiments were performed to explore whether DUSP2 is involved in the development of PCa. Results: A ceRNA network related to FOXA1 was constructed and comprised 18 lncRNAs, 5 miRNAs, and 44 mRNAs. The MAGI2-AS3~has-mir-106a/has-mir-204~DUSP2 ceRNA regulatory network relevant to the prognosis of PCa was obtained by analysis. We markedly distinguished the MAGI2-AS3/DUSP2 axis in the ceRNA. It will most likely become a clinical prognostic model and impact the changes in the tumor immune microenvironment of PCa. The abnormal MAGI2-AS3 expression level from the patients' blood manifested that it would be a novel potential diagnostic biomarker for PCa. Moreover, down-expressed DUSP2 suppressed the proliferation and migration of PCa cells. Conclusions: Our findings provide pivotal clues to understanding the role of the FOXA1-concerned ceRNA network in PCa. Simultaneously, this MAGI2-AS3/DUSP2 axis might be a new significant prognostic factor associated with the diagnosis and prognosis of PCa.

Effects of hypoxia on DNA hydroxymethylase Tet methylcytosine dioxygenase 2 in a KG-1 human acute myeloid leukemia cell line and its mechanism.

Hypoxia is involved in the epigenetic modification of leukemia. As an important DNA hydroxymethylase and a tumor suppressor gene, the expression regulating mechanism of Tet methylcytosine dioxygenase 2 (TET2) remains unclear. The aim of the present study was to explore whether hypoxia and hypoxia-inducible factor 1α (HIF-1α) regulate TET2 gene expression and its demethylation function in acute myeloid leukemia (AML). The human AML cell line KG-1 was used in the present study. The results demonstrated that hypoxia could increase proliferation, enhance metabolism and inhibit apoptosis in KG-1 cells, as detected by the cell counting kit-8 assay, lactate dehydrogenase assay and Annexin V-FITC/propidium iodide staining, respectively. Hypoxia reduced the genome methylation status in KG-1 cells detected using 5-methylcytosine and 5-hydroxymethylcytosine detection kits. In addition, HIF-1α overexpression increased TET2 expression, 5-hmC level and cyclin-dependent kinase inhibitor 2B [p15(INK4B)] gene demethylation compared with the HIF-1α non-overexpression group in KG-1 cells detected by reverse transcription-quantitative PCR, western blotting, 5-hydroxymethylcytosine detection kits and methylation-specific PCR, respectively. The inhibition of HIF-1α by inhibitor YC-1 reduced demethylation in KG-1 cells by decreasing TET2 expression. It was also revealed that HIF-1α could enhance TET2 transcriptional activity by binding to the hypoxia response element of the TET2 gene promoter region using chromatin immunoprecipitation and luciferase reporter gene assays. TET2 may be a potential target gene regulated by HIF-1α. Hypoxia was demonstrated to regulate the expression of TET2 by HIF-1α, which in turn affected the methylation and expression of downstream target genes and served a role in the occurrence and progression of leukemia. In the present study, the association between hypoxia metabolism and epigenetic regulation in AML was investigated and the findings provided a new idea and experimental basis for the diagnosis and treatment of hematologic malignancies.

Self-assembly gel-based dynamic response system for specific recognition of N-acetylneuraminic acid.

Sialic acids located at the terminal end of glycans are densely attached to cell surfaces and play crucial and distinctive roles in a variety of physiological and pathological processes, such as neural development, cell-cell interactions, autoimmunity and cancers. However, due to the subtle structural differences of sialic acid species and the complicated composition of glycans, the precise recognition of sialylated glycans is difficult. Here, a fluorescent dynamic response system based on a pyrene-conjugated histidine (PyHis) supramolecular gel is proposed. Driven by π-π stacking and intermolecular hydrogen bonds, PyHis exhibits a strong self-assembly ability and forms stable gels. It is found that introduction of N-acetylneuraminic acid (a typical sialic acid) can prevent this self-assembly process, whereas other monosaccharides or sialic acid analogs have no significant effect on it. Interestingly, a sialylated glycan also has a remarkable inhibitory effect on the gel formation, which highlights the high selectivity of the gel dynamic response system. Analysis of the mechanism reveals that the sialic acid or sialylated glycan can interact closely with two PyHis molecules stacked together in the assemblies via hydrogen bonding interactions, thereby preventing the ordered accumulation of the gelators. It is worth noting that the high-efficiency sialic acid recognition effect is not observed at the single molecule level but at the supramolecular level, indicating the unique superiority of the supramolecular self-assembly system in biomolecular recognition and response. This work shows the promising prospects of using supramolecular gels in assembly engineering, regenerative medicine, tumour cell sorting and cancer diagnosis.

Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study.

With the capability of inducing elevated expression of ACE2 (angiotensin-converting enzyme 2), the cellular receptor for severe acute respiratory syndrome coronavirus 2, angiotensin II receptor blockers (ARBs) or ACE inhibitors treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the effects of ARBs/ACE inhibitors on coronavirus disease 2019 (COVID-19) in a retrospective, single-center study. One hundred twenty-six patients with COVID-19 and preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine in Wuhan from January 5 to February 22, 2020, were retrospectively allocated to ARBs/ACE inhibitors group (n=43) and non-ARBs/ACE inhibitors group (n=83) according to their antihypertensive medication. One hundred twenty-five age- and sex-matched patients with COVID-19 without hypertension were randomly selected as nonhypertension controls. In addition, the medication history of 1942 patients with hypertension that were admitted to Hubei Provincial Hospital of Traditional Chinese Medicine from November 1 to December 31, 2019, before the COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical, and laboratory data were collected, analyzed, and compared between these groups. The frequency of ARBs/ACE inhibitors usage in patients with hypertension with or without COVID-19 were comparable. Among patients with COVID-19 and hypertension, those received either ARBs/ACE inhibitors or non-ARBs/ACE inhibitors had comparable blood pressure. However, ARBs/ACE inhibitors group had significantly lower concentrations of hs-CRP (high-sensitivity C-reactive protein; P=0.049) and PCT (procalcitonin, P=0.008). Furthermore, a lower proportion of critical patients (9.3% versus 22.9%; P=0.061) and a lower death rate (4.7% versus 13.3%; P=0.216) were observed in ARBs/ACE inhibitors group than non-ARBs/ACE inhibitors group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACE inhibitors in patients with COVID-19 and preexisting hypertension.

Clinicopathological and prognostic significance of platelet-to-lymphocyte ratio in patients with hepatocellular carcinoma.

The platelet-to-lymphocyte ratio (PLR) is reported to be a prognostic factor in multiple malignancies. The aim of this study was to assess its prognostic value in hepatocellular carcinoma (HCC). We performed comprehensive searches of electronic databases for relevant studies. A total of eleven studies comprising 2,507 patients were included. Elevated PLR was significantly associated with poor overall survival (OS) (HR = 1.78; 95% CI = 1.36-2.34; P < 0.001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 1.82; 95% CI = 1.56-2.13; P < 0.001). The findings from most subgroup analyses were consistent with those from the overall analysis. In addition, a high PLR correlated with tumor size > 3 cm, TNM stage, lymph node metastasis, distant metastasis, and vascular invasion. We therefore conclude that elevated pretreatment PLR may be predicative of a poor prognosis in patients with HCC.