Diagnostic value of neutrophil CD64, procalcitonin, and interleukin-6 in sepsis: a meta-analysis.

BACKGROUND: The aim of the study was to conduct a meta-analysis to evaluate the accuracy of neutrophil CD64, procalcitonin (PCT), and interleukin-6 (IL-6) as markers for the diagnosis of sepsis in adult patients. METHODS: Various databases were searched to collect published studies on the diagnosis of sepsis in adult patients using neutrophil CD64, PCT, and IL-6 levels. Utilizing the Stata SE 15.0 software, forest plots and the area under the summary receiver operating characteristic curves were drawn. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve (AUC) were calculated. RESULTS: Fifty-four articles were included in the study. The pooled sensitivity, specificity, and AUC of neutrophil CD64 for the diagnosis of sepsis were 0.88 (95% confidence interval [CI], 0.81-0.92), 0.88 (95% CI, 0.83-0.91), and 0.94 (95% CI, 0.91-0.96), respectively. The pooled sensitivity, specificity, and AUC of PCT for the diagnosis of sepsis were 0.82 (95% CI, 0.78-0.85), 0.78 (95% CI, 0.74-0.82), and 0.87 (95% CI, 0.83-0.89), respectively. Subgroup analysis showed that the AUC for PCT diagnosis of intensive care unit (ICU) sepsis was 0.86 (95% CI, 0.83-0.89) and the AUC for PCT diagnosis of non-ICU sepsis was 0.82 (95% CI, 0.78-0.85). The pooled sensitivity, specificity, and AUC of IL-6 for the diagnosis of sepsis were 0.72 (95% CI, 0.65-0.78), 0.70 (95% CI, 0.62-0.76), and 0.77 (95% CI, 0.73-0.80), respectively. CONCLUSIONS: Of the three biomarkers studied, neutrophil CD64 showed the highest diagnostic value for sepsis, followed by PCT, and IL-6. On the other hand, PCT showed a better diagnostic potential for the diagnosis of sepsis in patients with severe conditions compared with that in patients with non-severe conditions.

Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.

Timely analysis of the laboratory characteristics associated with 2019 novel coronavirus pneumonia (COVID-19) can assist with clinical diagnosis and prognosis. This study is a collection of clinical data from 54 hospitalized adult patients diagnosed with COVID-19 in the Zhongfa Xincheng district of China at Tongji Hospital of Huazhong University of Science and Technology from January 28, 2020 to February 11, 2020. The average age of the patients was 61.8 ± 14.5 years, and the predominant age group was 50-79. The proportion of critical-type patients with comorbidities was higher than that of severe-type patients. Lymphocyte counts were significantly reduced in routine bloodwork for all patients, but significantly lower in critical-type patients than that in severe-type patients. Prolongation of prothrombin times (PT) and elevation of fibrinogen degradation products (FDPs) and D-dimers (D-Ds) were detected in coagulation function tests, and more significant changes were observed in critical-type patients compared to severe-type patients. Serum ferritin levels were sensitive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but could not be used for disease assessment. In addition, levels of two inflammatory factors, soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) were significantly increased in all patients, but higher in critical-type patients than in severe-type patients. Moreover, kidney injury was the second-most common organ affected by COVID-19 followed by heart and liver. Kidney and heart injury were more severe in critical-type patients than in severe-type patients. All of the 31 severe-type patients recovered. Of the critical-type patients, six died and 17 recovered. The length of hospital stay for critical-type patients was significantly longer for severe-type patients. In summary, increased lymphocyte counts, prolonged PT, secondary increases in fibrinolytic activity and increases in sIL-2R and IL-6 are typical features of COVID-19 and are associated with disease severity.

Tumor-Promoting Activity of Long Noncoding RNA LINC00466 in Lung Adenocarcinoma via miR-144-Regulated HOXA10 Axis.

Previous investigations have implicated long noncoding RNAs in lung adenocarcinoma, which is an aggressive disease with poor prognosis and high mortality. Through the alteration of lung adenocarcinoma-related long noncoding RNA and miRNA based on microarray analysis, our aim was to understand the role of LINC00466 and miR-144 in lung adenocarcinoma progression. The relationship among LINC00466, miR-144, and HOXA10 was also verified. Moreover, to examine whether the LINC00466/miR-144/HOXA10 axis contributed to the cellular processes in lung adenocarcinoma, A549 and XWLC-05 cells were transduced with siRNA LINC00466, siRNA HOXA10, or miR-144 mimic plasmids. Highly expressed LINC00466 and HOXA10 and lowly expressed miR-144 were eventually revealed in lung adenocarcinoma tissues. HOXA10 was down-regulated in response to the overexpression of miR-144, whereas inhibition of LINC00466 decreased its binding to miR-144, thereby up-regulating miR-144, which, in turn, halted the lung adenocarcinoma progression. LINC00466 silencing or miR-144 up-regulation exerted an inhibitory role in the tumorigenicity, invasion, migration, and proliferation, and it also promoted apoptosis of lung adenocarcinoma cells. Furthermore, tumor formation was inhibited by knockdown of LINC00466 or overexpression of miR-144. Taken together, LINC00466 could restrain the miR-144 expression to up-regulate HOXA10 and, therefore, promote lung adenocarcinoma.

Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era.

Currently, chemoimmunotherapy is the first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, only 0.8%-2.5% of the patients presented complete response after chemoimmunotherapy. Considering that ES-SCLC is highly sensitive to radiotherapy, the addition of radiotherapy after first-line treatment for ES-SCLC could further improve local control, which may be beneficial for patients' survival. Prior studies have shown that consolidative thoracic radiotherapy (cTRT) can decrease disease progression and improve overall survival in patients with ES-SCLC who respond well to chemotherapy. However, the efficacy and safety of cTRT in the immunotherapy era remain unclear owing to a lack of prospective studies. Prophylactic cranial irradiation (PCI) has been shown to decrease brain metastasis (BM) and prolong survival in patients with limited-stage SCLC in previous reports. However, according to current guidelines, PCI is not commonly recommended for ES-SCLC. Immunotherapy has the potential to reduce the incidence of BM. Whether PCI can be replaced with regular magnetic resonance imaging surveillance for ES-SCLC in the era of immunotherapy remains controversial. Whole brain radiation therapy (WBRT) is the standard treatment for BM in SCLC patients. Stereotactic radiosurgery (SRS) has shown promise in the treatment of limited BM. Considering the potential of immunotherapy to decrease BM, it is controversial whether SRS can replace WBRT for limited BM in the immunotherapy era. Additionally, with the addition of immunotherapy, the role of palliative radiotherapy may be weakened in patients with asymptomatic metastatic lesions. However, it is still indispensable and urgent for patients with obvious symptoms of metastatic disease, such as spinal cord compression, superior vena cava syndrome, lobar obstruction, and weight-bearing metastases, which may critically damage the quality of life and prognosis. To improve the outcome of ES-SCLC, we discuss the feasibility of radiotherapy, including cTRT, PCI, WBRT/SRS, and palliative radiotherapy with immunotherapy based on existing evidence, which may offer specific prospects for further randomized trials and clinical applications.

Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and is characterized by extensive metastasis and poor prognosis. Extracellular vesicles (EVs) derived from endothelial cells carrying microRNAs (miRNAs/miRs) have diagnostic and therapeutic potential for NSCLC. We herein investigate the potential of EVs derived from human umbilical vein endothelial cells (HUVECs) to transfer miR-203 to affect the progression of NSCLC. miR-203 and p21 were poorly expressed while DTL was highly expressed both in NSCLC tissues and cell lines. We employed CCK-8 proliferation, colony formation, and Transwell migration and invasion assays to evaluate the effects of miR-203 on NSCLC cell behaviors using loss- and gain-function approaches. EVs were isolated from HUVECs and then co-cultured with the A549 cells transfected with mimic-NC or miR-203 inhibitor. miR-203 targeted DTL and downregulated its expression, subsequently leading to increased stability of p21 which is a tumor suppressor. EV-enriched miR-203 from HUVECs suppressed malignant phenotypes of NSCLC cells and delayed tumor growth. In conclusion, miR-203 from HUVEC-derived EVs exerts inhibitory effects on the progression of NSCLC by targeting DTL and promoting p21 protein stability.

HOXA10 promotion of HDAC1 underpins the development of lung adenocarcinoma through the DNMT1-KLF4 axis.

BACKGROUND: Previous research has highlighted the ability of Homeobox A10 (HOXA10) to the promote proliferation, migration, and epithelial-mesenchymal transformation of various cancers, including lung adenocarcinoma (LAD), which is characterized by an aggressive disease course that exhibits rapid proliferation and migration, with studies suggesting histone deacetylase 1 (HDAC1) to be a downstream mediator of HOXA10. The current study aimed to investigate the mechanism by which HOXA10-mediated HDAC1 influences the development of LAD. METHODS: The expression patterns of HOXA10, HDAC1, DNA methyltransferase 1 (DNMT1), and Kruppel-like factor 4 (KLF4) were determined. Additionally, the effect of HOXA10, HDAC1, or DNMT1 on invasive phenotypes of LAD was analyzed using depletion experiments. The interactions among HOXA10, HDAC1, DNMT1, and KLF4 were evaluated via chromatin immunoprecipitation, dual luciferase assay or co-immunoprecipitation. Furthermore, the tumorigenic ability of the LAD cells following HOXA10 silencing and/or HDAC1 overexpression in vivo was also investigated. RESULTS: In the LAD tissues and cells, HOXA10, HDAC1, and DNMT1 all exhibited high levels of expression, while KLF4 was poorly expressed. HOXA10 silencing inhibited the expression of HDAC1, reduced LAD cell proliferation, migration, and invasion, and promoted the apoptosis. HDAC1 promoted DNMT1 expression through deacetylation, and DNMT1 inhibited the KLF4 expression through DNA methyltransferase. The in vitro findings were further attested through the use of in vivo assays. CONCLUSION: Taken together, the key observations of the current study highlight the role of HOXA10 and HDAC1 in promoting the proliferation and migration of LAD cells. HOXA10-induced upregulation of HDAC1 interacts with DNMT1-KLF4 axis, while the inhibition of HOXA10 or HDAC1 represents a promising anti-tumor therapy target for LAD.

A novel circular RNA hsa_circ_0020123 exerts oncogenic properties through suppression of miR-144 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide, while circulatory. Circular RNAs (circRNAs) are found to play important roles in cancer initiation and development. Herein, a novel functional circRNA hsa_circ_0020123 had been identified in NSCLC progression in this study, and elevated hsa_circ_0020123 expression could be observed in cancer tissues compared with that in matched normal lung tissues. Moreover, up-regulation of hsa_circ_0020123 was recognized to be closely associated with a poor differentiation degree, lymph node metastasis, a high TNM stage and dismal prognosis for NSCLC patients. Typically, knockdown of hsa_circ_0020123 could inhibit the NSCLC growth and metastasis both in vitro and in vivo, which could be reversed by the hsa_circ_0020123 overexpression. Importantly, miR-144 was identified as the hsa_circ_0020123-associated miRNA through performing RNA in vivo precipitation (RIP) in NSCLC cells using a biotin-labeled hsa_circ_0020123 probe. Besides, our results suggested that, miR-144 suppression had determined the oncogenic properties mediated by hsa_circ_0020123. In addition, hsa_circ_0020123 could upregulate ZEB1 and EZH2 through competitively binding with miR-144. Finally, the administration of hsa_circ_0020123 siRNA could suppress the growth and metastasis in NSCLC-bearing mice in vivo. In conclusion, the hsa_circ_0020123-miR-144-ZEB1/EZH2 axis is critical for NSCLC progression, which indicates that hsa_circ_0020123 is a potential target for NSCLC treatment.

IDH1 mutation promotes lung cancer cell proliferation through methylation of Fibulin-5.

Mutation in isocitrate dehydrogenase (IDH) leads to an aberrant function of the enzyme, leading to the production of hydroxyglutarate, as well as changes in cellular metabolism, DNA methylation and histone modification. Previous studies uncovered mutations in IDH1 in several malignancies, with the most frequent mutation being IDH1 R132H. It has been demonstrated that IDH1 expression is induced in non-small-cell lung cancer (NSCLC). However, the contribution of IDH1 mutation in the malignant transformation and development of NSCLC is unclear. In our study, we show that IDH1 R132H enhanced the migration and proliferation of NSCLC cells. Moreover, IDH1 R132H was a crucial modulator of 2-hydroxyglutarate, whose production from cells with IDH1 mutation promoted the binding of DNA-methyltransferase 1 (DNMT1) to the Fibulin-5 promoter, leading to its methylation. As a result, Fibulin-5 silencing in cells with IDH1 mutation enhanced the migration and proliferation of NSCLC cells. We show that the IDH1 mutation was present in tissues sampled from patients with NSCLC, which was reversely linked to Fibulin-5 expression. In this study, we suggest an innovative model for IDH1 R132H/Fibulin-5 pathway, which could throw light upon the activity of IDH1 R132H in NSCLC.

Effect of SLC34A2 gene mutation on extracellular phosphorus transport in PAM alveolar epithelial cells.

A mutation in the IIb sodium phosphate transporter SLC34A2 gene has recently been described in pulmonary alveolar microlithiasis (PAM) patients. Experiments in this study were aimed at confirming the role of the gene product in PAM by comparing phosphorylated products in extracellular fluid of alveolar epithelial cells overexpressing the SLC34A2 gene or its mutated version. Eukaryotic expression vectors were constructed and transfected into A549 human alveolar epithelial cells. There were three groups of cells including those transfected with empty vector plasmid pcDNA3.1(+) (plasmid control group), those transfected with normal SLC34A2 gene expressed from pcDNA3.1 (normal control group), and those transfected with a version of the PAM SLC34A2 gene linked to the pcDNA3.1(+) (PAM group). Transfection efficiencies were detected by reverse transcription-polymerase chain reaction (RT-PCR). At 48 h after transfection, the concentration of inorganic phosphorus in the culture medium was detected using an automatic biochemical analyzer. Our results showed the concentration of inorganic phosphorus in the supernatant of the normal control group was significantly lower than that in the plasmid control and PAM groups (P<0.01), and the concentration in the PAM group was significantly lower than that in the plasmid control group (P<0.01). Based on our findings it is possible that the SLC34A2 gene mutation is the cause of the pathogenic changes observed in PAM patients, given that the function of the phosphate transporter seems to be affected and it is conceivable that it would lead to extracellular fluid alterations in vivo.

LncRNA H19-elevated LIN28B promotes lung cancer progression through sequestering miR-196b.

LncRNA H19 is involved in the development of multiple cancers. Here, we firstly provide new evidence that H19 can induce LIN28B, a conserved RNA binding protein, to accelerate lung cancer growth through sponging miR-196b. Abundance in LIN28B was observed in clinical lung cancer samples. A positive link was observed between H19 and LIN28B in clinical lung cancer samples. In lung cancer cells, H19 was capable of increasing LIN28B expression. Mechanistically, miR-196b directly targeted LIN28B to inhibit LIN28B expression. H19 was capable of promoting LIN28B expression through sequestering miR-196b. Functionally, H19-increased LIN28B conferred the cell proliferation of lung cancer. Our finding indicates that H19 depresses miR-196b to elevate LIN28B, resulting in accelerating cell proliferation in lung cancer.

Maternal exposure to farming environment protects offspring against allergic diseases by modulating the neonatal TLR-Tregs-Th axis.

BACKGROUND: As the development of urbanization in China, the morbidity of allergic disease rise up prominently even in children, which may be partially associated with the excessively clean environment. It has been reported that common microorganism in rural environment shows protective effects on allergic disease by modulating TLRs-Tregs/Th cell axis. But the mechanism of this protection still needs to be elucidated in detail. We investigated the effects of maternal exposure to farming environment on the neonatal innate immune system, especially on the TLR-Treg-Th (Th1, Th2, Th9, and Th17) axis, in the Jilin province of China. METHODS: Eighty-four non-farming and 42 farming pregnant women were recruited. Endotoxins and glucans in dust from the living rooms of the pregnant mothers were measured. Cord blood mononuclear cells were challenged with phytohemagglutinin, lipopolysaccharide, or peptidoglycan. Proliferative response of lymphocyte was measured by 3H-TdR incorporation methods, CD4 + CD25 + FOXP3 + T cells percentage was assessed with flow cytometry, Tregs specific genes (FOXP3, LAG3, GITR, CTLA-4 and TGF-ß) and TLR2, TLR4 genes expression were detected by RT-PCR, specific cytokines of Th1, Th2, Th9, Th17 and Tregs were measured with flow cytometer, suppressive capacity of Tregs was tested by culturing with effector cells in vitro, and TLR2/4 gene polymorphism was detected. RESULTS: Higher endotoxin content was observed in the living rooms of the farming mothers. Compared with that in the non-farming group, in farming neonatal CBMCs, lymphocyte proliferation declined; the IFN-γ/IL-13 ratio increased; and the quantity of Tregs and gene expression of FOXP3, GITR, CTLA4 and TLR2 increased significantly (P < 0.05). Isolated Tregs suppressed the proliferation of effector T cells and IL-13 production more strongly in vitro (P = 0.04, 0.03, respectively), and the TLR2 polymorphism affected FOXP3 expression and IFN-γ and IL-13 production. CONCLUSIONS: Maternal exposure to farming affected the quantity and function of neonatal Tregs upon stimulation with PPG and LPS, which partly contributed to reducing the risk for allergic diseases in the offspring. The results of our study will lay the theoretical foundation for allergic disease prevention in early life.

Sulforaphane prevents bleomycin­induced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2­related factor­2 activation.

Lung fibrosis is associated with inflammation, apoptosis and oxidative damage. The transcription factor nuclear factor erythroid 2­related factor­2 (Nrf2) prevents damage to cells from oxidative stress by regulating the expression of antioxidant proteins. Sulforaphane (SFN), an Nrf2 activator, additionally regulates excessive oxidative stress by promoting the expression of endogenous antioxidants. The present study investigated if SFN protects against lung injury induced by bleomycin (BLM). The secondary aim of the present study was to assess if this protection mechanism involves upregulation of Nrf2 and its downstream antioxidants. Pulmonary fibrosis was induced in C57/BL6 mice by intratracheal instillation of BLM. BLM and age­matched control mice were treated with or without a daily dose of 0.5 mg/kg SFN until sacrifice. On days 7 and 28, mice were assessed for induction of apoptosis, inflammation, fibrosis, oxidative damage and Nrf2 expression in the lungs. The lungs were investigated with histological techniques including haematoxylin and eosin staining, Masson's trichrome staining and terminal deoxynucleotidyl transferase UTP nick end labeling. Inflammatory, fibrotic and apoptotic processes were confirmed by western blot analysis for interleukin­1ß, tumor necrosis factor­α, transforming growth factor­ß and caspase­3 protein expressions. Furthermore, protein levels of 3­nitro­tyrosine, 4­hydroxynonenal, superoxide dismutase 1 and catalase were investigated by western blot analysis. It was demonstrated that pulmonary fibrosis induced by BLM significantly increased apoptosis, inflammation, fibrosis and oxidative stress in the lungs at days 7 and 28. Notably, SFN treatment significantly attenuated the infiltration of the inflammatory cells, collagen accumulation, epithelial cell apoptosis and oxidative stress in the lungs. In addition, SFN treatment increased expression of the Nrf2 gene and its downstream targets. In conclusion, these results suggested that SFN treatment of pulmonary fibrosis mouse models may attenuate alveolitis, fibrosis, apoptosis and lung oxidative stress by increasing the expression of antioxidant enzymes, including NAPDH quinone oxidoreductase, heme oxygenase­1, superoxide dismutase and catalase, via upregulation of Nrf2 gene expression. Thus, the results from the present study may facilitate the development of therapies for BLM­toxicity and pulmonary fibrosis.

Multi-organ involvement of Sweet's syndrome: a case report and literature review.

The hallmark of Sweet's syndrome (SS) is the infiltration of mature neutrophils in the upper dermis. We herein report a case of SS with multi-organ involvement. A 32-year-old man presented with fever, anemia and dyspnea. He was given antibiotics, without any improvements. Later, a number of erythematous lesions appeared, accompanied by deteriorating respiratory and cardiovascular functions. A diagnosis of SS was confirmed on a skin biopsy, and the patient was given corticosteroids, the dose of which was reduced after one month. The organ function subsequently deteriorated, and he ultimately died of multi-organ failure. Early recognition of SS with multi-organ involvement is important in patients with SS.

A pedigree with pulmonary alveolar microlithiasis: a clinical case report and literature review.

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease characterized by the presence of innumerable calcium phosphate microliths in the alveoli. Clinical-radiological dissociation is an important hallmark of this disease. Most PAM patients are asymptomatic and pulmonary tissue changes are discovered incidentally. PAM is pathologically attributable to the formation and aggregation of calcium phosphate microliths in the alveoli after mutations in the SLC34A2 gene (the type IIb sodium-phosphate cotransporter gene) coding NaPi-IIb. In the clinical work, we discovered an inbred pedigree with PAM, which include four PAM siblings. We performed a sequence analysis of the SLC34A2 gene in all members of this PAM pedigree and found that a homozygous mutation c.575C > A (p.T192 K) in exon 6 was involved. To the best of our knowledge, this study was the first to discover nucleotide mutations in exon 6 in Asians.

Knockdown of HMGN5 expression by RNA interference induces cell cycle arrest in human lung cancer cells.

HMGN5 is a typical member of the HMGN (high mobility group nucleosome-binding protein) family which may function as a nucleosomal binding and transcriptional activating protein. Overexpression of HMGN5 has been observed in several human tumors but its role in tumorigenesis has not been fully clarified. To investigate its significance for human lung cancer progression, we successfully constructed a shRNA expression lentiviral vector in which sense and antisense sequences targeting the human HMGN5 were linked with a 9-nucleotide loop. Inhibitory effects of siRNA on endogenous HMGN5 gene expression and protein synthesis were demonstrated via real-time RT-PCR and western blotting. We found HMGN5 silencing to significantly inhibit A549 and H1299 cell proliferation assessed by MTT, BrdU incorporation and colony formation assays. Furthermore, flow cytometry analysis showed that specific knockdown of HMGN5 slowed down the cell cycle at the G0/G1 phase and decreased the populations of A549 and H1299 cells at the S and G2/M phases. Taken together, these results suggest that HMGN5 is directly involved in regulation cell proliferation in A549 and H1299 cells by influencing signaling pathways involved in cell cycle progression. Thus, our finding suggests that targeting HMGN5 may be an effective strategy for human lung cancer treatment.