Efficacy and Safety of Nanoadministration in the Treatment of Non-Small-Cell Lung Cancer Is Good to Some Extent: A Systematic Review and Meta-Analysis.

Purpose: The purpose of this study was to evaluate the efficacy and safety of a nanodrug delivery regimen compared with conventional drug administration for the treatment of lung cancer. Materials and Methods: Studies were retrieved through PubMed, Web of Science, and ScienceDirect. Primary and secondary outcome measures, including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events, were extracted from the retrieved literature and systematically evaluated. Results: Six trials, including 4806 advanced non-small-cell lung cancer patients, were included in this study. Compared with conventional drug administration in the treatment of lung cancer, the nanodrug delivery regimen improved the ORR (risk ratio = 1.43, 95% confidence interval (CI) = 1.25-1.63, p ≤ 0.001), prolonged PFS (hazard ratio (HR) = 0.83, 95% CI = 0.76-0.92, p ≤ 0.001), and obtained superior OS (HR = 0.91, 95% CI = 0.83-0.99, p ≤ 0.001). Regarding safety, the incidence of neutropenia, alopecia, sensory neuropathy, myalgia, and arthralgia was lower in the nanoadministration group, but the risk of thrombocytopenia, anaemia, and nausea was increased. Conclusion: Nanodrug administration is safe and effective in patients with non-small-cell lung cancer to some extent.

Seven autophagy-related lncRNAs are associated with the tumor immune microenvironment in predicting survival risk of nonsmall cell lung cancer.

BACKGROUND: Nonsmall cell lung cancer (NSCLC) ranks first among global cancer-related deaths. Despite the emergence of various immunological and targeted therapies, immune tolerance remains a barrier to treatment. METHODS: It has been found that this obstacle can be overcome by targeting autophagy-related genes (ATGs). ATGs were screened by coexpression analysis and the genes related to the prognosis of lung cancer were screened using Kaplan-Meier (K-M) survival analysis, univariate Cox regression and multivariate Cox regression. The prognostic risk model of ATGs was constructed and verified using K-M survival analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: The prognostic risk model of ATGs was constructed. Gene set enrichment analysis (GSEA) showed that the function and pathway of ATG enrichment were closely related to immune cell function. CIBERSORT, LM22 matrix and Pearson correlation analysis showed that risk signals were significantly correlated with immune cell infiltration and immune checkpoint genes. CONCLUSIONS: We identified and independently verified the ATG (AL691432.2, MMP2-AS1, AC124067.2, CRNDE, ABALON, AL161431.1, NKILA) in NSCLC patients and found that immune regulation in the tumor microenvironment is closely related to this gene.

ARL14 as a Prognostic Biomarker in Non-Small Cell Lung Cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The mechanisms underlying NSCLC initiation and progression require further investigation. The purpose of this study was to investigate the role of ADP ribosylation factor-like GTPase 14 (ARL14) related to the progression of NSCLC. PATIENTS AND METHODS: We analyzed the correlation between clinical characteristics and ARL14 expression using data from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was conducted to evaluate the prognostic value of ARL14 in NSCLC. Functions of ARL14 were identified by enrichment analysis. The relationship between ARL14 expression and immune cell infiltration was also studied. Furthermore, ARL14 expression was examined using immunohistochemistry, and its clinical significance was analyzed in 120 patients with NSCLC. RESULTS: Our study revealed that the expression level of ARL14 in patients with NSCLC was higher than that in normal tissues. Using TCGA data, higher ARL14 expression in lung adenocarcinoma was associated with residual tumor (P = 0.017), while it was associated with age (P = 0.003) and N stage (P = 0.009) in lung squamous cell carcinoma. Similar results were obtained from 120 patients with NSCLC. High ARL14 expression was associated with poor overall survival and progression-free survival in NSCLC. Multivariate analysis revealed that ARL14 was an independent risk factor for patients with NSCLC. Functional enrichment analysis indicated that ARL14 was related to the occurrence and development of tumors. CONCLUSION: Increased ARL14 expression was considerably correlated with poor survival in NSCLC, and it might be a promising prognostic biomarker for NSCLC.

Effect of Methylation Status of lncRNA-MALAT1 and MicroRNA-146a on Pulmonary Function and Expression Level of COX2 in Patients With Chronic Obstructive Pulmonary Disease.

This study aimed to investigate the role of methylation of MALAT1 and miR-146a in the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD patients were grouped according to their methylation status of MALAT1 and miR-146a promoters, and we found that forced vital capacity, volume that has been exhaled at the end of the first second of forced expiration, and diffusion capacity for carbon monoxide were the highest in the MALAT1 HYPO + miR-146a HYPER group and lowest in the MALAT1 HYPER + miR-146a HYPO group, and COPD patients with hypermethylated MALAT1 showed lower expression of MALAT1 than that in the COPD patients with hypomethylated MALAT1. Meanwhile, miR-146a was the most significantly upregulated in the MALAT1 HYPER + miR-146a HYPO group and the most significantly downregulated in the MALAT1 HYPO + miR-146a HYPER group. Both prostaglandin E1 and cyclooxygenase 2 (COX2) expression were the highest in the MALAT1 HYPO + miR-146a HYPER group and the lowest in the MALAT1 HYPER + miR-146a HYPO group. In conclusion, our results established a MALAT1/miR-146a/COX2 signaling axis. The overexpression of MALAT1 could increase the expression of COX2 by inhibiting the expression of miR-146a, thus affecting the pulmonary function of COPD patients.

Integrated analysis of the molecular mechanisms in idiopathic pulmonary fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonia. Some miRNAs may be associated with IPF and may affect the occurrence and development of IPF in various pathways. Many miRNAs and genes that may be involved in the development of IPF have been discovered using chip and high throughput technologies. Methods: We analyzed one miRNA and four mRNA databases. We identified hub genes and pathways related to IPF using GO, KEGG enrichment analysis, gene set variation analysis (GSVA), PPI network construction, and hub gene analysis. A comprehensive analysis of differentially expressed miRNAs (DEMs), predicted miRNA target genes, and differentially expressed genes (DEGs) led to the creation of a miRNA-mRNA regulatory network in IPF. Results: We found 203 DEGs and 165 DEMs that were associated with IPF. The findings of enrichment analyses showed that these DEGs were mainly involved in antimicrobial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptide, extracellular matrix organization, cell killing, and organ or tissue specific immune response. The VEGFA, CDH5, and WNT3A genes overlapped between hub genes and the miRNA-mRNA regulatory network. The miRNAs including miR-199b-5p, miR-140-5p, miR-199a-5p, miR-125A-5p, and miR-107 that we predicted would regulate the VEGFA, CDH5, and WNT3A genes, which were also associated with IPF or other fibrosis-related diseases. GSVA indicated that metabolic processes of UTP and IMP, immune response, regulation of Th2 cell cytokine production, and positive regulation of NK cell-mediated immunity are associated with the pathogenesis and treatment of IPF. These pathways also interact with VEGFA, CDH5, and WNT3A. Conclusion: These findings provide a new research direction for the diagnosis and treatment of IPF.

Nivolumab monotherapy or combination therapy with ipilimumab for lung cancer: a systemic review and meta-analysis.

BACKGROUND: The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS: We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS: The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS: Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.

Association Between NAT2 Polymorphism and Lung Cancer Risk: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related death worldwide and has a high incidence rate. N-Acetyltransferase 2 (NAT2) is a polymorphic xenobiotic enzyme, which can catalyze N-acetylation and O-acetylation of various carcinogens such as aromatic, heterocyclic amines and hydrazines. At present, many studies have explored the effects of NAT2 polymorphism on lung cancer, but we found inconsistent results. We researched 18 published studies, involving 4,016 patients and 5,469 controls, to more accurately assess the effects of NAT2 polymorphism on lung cancer risk and to investigate whether smoking is associated. We used STATA software to analyze the extracted data and used STATA for subgroup analysis, sensitivity analysis, and to perform publication bias tests. To determine the correlation, we used the crude odds ratio (ORs) with 95% confidence interval (CIs). Our study was prospectively registered in PROSPERO (CRD42020159737). The odds ratio was 1.53 (95% CI: 1.21-1.95, I² = 45.2%, P=0.104) for the NAT2 slow + intermediate phenotype versus rapid phenotype. The results suggested that people with NAT2 non-rapid (slow + intermediate) phenotype have a significantly increased risk of lung cancer. In addition, NAT2 rapid phenotype was significantly associated with reduced risk of lung cancer, compared with slow phenotype or intermediate phenotype (slow phenotype vs . rapid phenotype: OR: 1.61, 95% CI: 1.07-2.42, I²= 50%, P= 0.075; intermediate phenotype vs . rapid phenotype: OR: 1.47, 95% CI: 1.15-1.88, I²= 40.3%, P= 0.137).

Microbiota Imbalance Contributes to COPD Deterioration by Enhancing IL-17a Production via miR-122 and miR-30a.

The changes of microbiota in lungs could change interleukin-17a (IL-17a) expression by altering microRNAs (miRNAs) profile, thus contributing to the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we aimed to study molecular mechanisms' underlying effect of microbiota imbalance on COPD deterioration. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to analyze expression of miRNAs and IL-17a mRNA. ELISA was used to evaluate abundance of IL-17a in plasma, peripheral blood monocyte, and sputum of COPD mice and patients. Luciferase assay was performed to explore underlying molecular mechanisms. The expression of miR-122, miR-30a, and miR-99b were remarkably decreased in COPD mice, while the expression of IL-17a was notably increased in plasma, peripheral blood monocytes, and lung tissues of COPD mice. The levels of Lactobacillus/Moraxella and IL-17a expression were significantly enhanced in sputum of exacerbated COPD patients, along with notably decreased expression of miR-122 and miR-30a. Luciferase assay confirmed that miR-122 and miR-30a played an inhibitory role in IL-17a expression. We identified miR-122 and miR-30a as differentially expressed miRNAs in sputum and plasma of COPD patients in exacerbation-month12 group. Furthermore, downregulated miR-122 and miR-30a expression associated with microbiota imbalance may contribute to COPD deterioration by enhancing IL-17a production.

Repeated successful vaginal delivery in a pregnant woman with unrepaired ectopia vesicae and split pelvis: a case study.

Ectopia vesicae, or bladder exstrophy, is a rare malformation, more frequently found in males. Very few cases of pregnancy with unrepaired ectopia vesicae have been reported in literature. The majority of these pregnant women with ectopia vesicae have terminated their pregnancies by cesarean section due to malpresentation, preterm labor or other indications. Clemetson concluded that cesarean section was the preferable method of term delivery to avoid postpartum prolapse. We have a different opinion on this because we had an interesting case. A woman with unrepaired ectopia vesicae had two successful vaginal deliveries, in 2009 and 2019 respectively. She recovered well and did not have any symptoms or signs of pelvic organ prolapse (POP) so far. CASE PRESENTATION: Let us present this woman with ectopia vesicae who had four pregnancies; two spontaneous abortions and two vaginal deliveries. In 2009, she had a successful vaginal delivery at Yantai Harbor Hospital where the first author worked at that time. She met the first author again surprisingly, during her third trimester in 2019. She had a spacious pelvis and pendulous abdomen. In this fourth pregnancy, the fetus changed its presentation frequently. Still, she had the second vaginal delivery successfully. She recovered fully after delivery and did not have any symptoms or signs of POP. As far as we know, this is the first case that a patient with ectopia vesicae who has been observed for such a long time after multiple vaginal deliveries. CONCLUSIONS: Doctors must evaluate the risk of vaginal delivery or cesarean section and consider maternal-neonatal health. Prior to this, women with repaired or unrepaired ectopia vesicae usually delivered their babies by cesarean section. Our practice shows that vaginal delivery is also a safe and feasible choice for some of these patients, especially for those with unrepaired, mild types of ectopia vesicae who experience no other dangerous or uncomfortable symptoms.

Estrogen administration reduces the risk of pulmonary arterial hypertension by modulating the miR-133a signaling pathways in rats.

We aimed to investigate how estrogen (ES) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH) potentially by reducing the extent of vascular remodeling in females. HE assay, Western Blot, IHC, and real-time PCR were carried out to observe the role of ES in regulating miR-133a expression and the levels of MYOSLID, SRF, CTGF, and vascular remodeling in rats. In addition, MTT assay and flow cytometry were utilized to observe how ES affects cell proliferation and cell cycle in PAH. Moreover, luciferase assays were carried out to clarity the regulatory relationship between miR-133a and its downstream targets. ES administration relieved the deregulation of miR-133a, MYOSLID, SRF, and CTGF in PAH rats. In addition, ES also reduced the thickening of blood vessels in PAH rats. ES could activate miR-133a promoter and arrest the cells in the G0/G1 cycle, thus dose-dependently suppressing the proliferation of cells. In addition, the presence of ES, MYOSLID siRNA, or miR-133a precursor all altered the expression of MYOSLID, SP1, SRF, and CTGF, thus establishing a molecular signaling pathway among these factors. Furthermore, miR-133a could bind to SP1, MYOSLID, SRF, and CTGF to reduce their expression. Moreover, SRF was proved to function as an activator of miR-133a promoter. Two feedback loops were established in this study: a negative feedback loop between SRF and miR-133a, and a positive loop among miR-133a/SRF/MLK1/MYOSLID. ES treatment upregulates miR-133a expression and reduces the incidence of PAH and vascular remodeling.

Wet Chemical Synthesis of Silica Nanosheets via Ethyl Acetate-Mediated Hydrolysis of Silica Precursors and Their Applications.

Freestanding and transferable silica nanosheets with thicknesses of ≈5-7 nm are prepared via ethyl acetate-mediated hydrolysis of silica precursors in aqueous solution. The resulting silica nanosheets have shown many potential applications. For example, they can be used as the support film on the finer mesh grids for transmission electron microscopy imaging and as the precursor for the synthesis of silicon nanosheets.

[Establishment of multiple quantitative fluorescent polymerase chain reaction assay and its application in rapid prenatal diagnosis of common chromosome aneuploidies].

OBJECTIVE: To establish the multiple quantitative fluorescent polymerase chain reaction (QF-PCR) assay and evaluate its clinical application in prenatal diagnosis. METHODS: Totally 170 samples were collected between May 2008 and July 2009 in prenatal center of Peking Union Medical College Hospital; 123 of them were amniotic fluid, 9 were chorionic villous samples, 20 were fetal blood and 18 were villi from aborted fetuses. All samples were from women of Han nationality, with mean age of (34.1 ± 4.6) years old, and with mean gestational age of (19.6 ± 1.0) weeks. Cytogenetic cultures and karyotyping were made to every sample. Genomic DNA was extracted from the samples. The sequences of twenty short tandem repeat (STR) markers were designed according to the GenBank and references, including 6 STR markers in chromosome 21, 4 in chromosome 18, 4 in chromosome 13, 4 in chromosome X, 1 in chromosome Y and 1 universal marker in both X and Y chromosome. Each sample was amplified by two sets of multiple QF-PCR, which included 4 STR markers in each of 21, 18, 13 and sex chromosomes. If the result was uninformative, the third set of another 4 STR markers was added. RESULTS: (1) Karyotyping. Cytogenetic analysis were made for all the 170 samples, 151 (89%) of which were normal, and 19 (11%) were abnormal. (2) QF-PCR assay. 167 (98%) samples were detected by QF-PCR. The results were obtained within 2 - 3 days after sampling. 134 samples were proved normal by QF-PCR, which was consistent with karyotyping. Among the 19 abnormal karyotype samples, 18 were detected as abnormal(eight were 21-trisomy, three were 18-trisomy)by QF-PCR. Among the 167 samples, 150 (90%) were detected using the first and second set of STR mixtures, and 3 (2%) were detected when the third set of STR was added. The remain 14 (8%) were uninformative. (3) The diagnostic efficiency of QF-PCR. The sensitivity of QF-PCR in prenatal diagnosis of common aneuploidities was 95%, the specificity, the false positive rate, the false negative rate, the positive predictive value and negative predictive value were 100%, 0, 5%, 100% and 99%, respectively. (4) Autosome and sex chromosome detection by QF-PCR. Among all the STR markers, D21S1270 and D21S1411 had the highest heterozygosities in chromosome 21, and DXS8377 had the highest in sex chromosome. The amplifications were stable. CONCLUSION: Multiple QF-PCR assay is a valid alternative in rapid prenatal diagnosis of common chromosome aneuploidies. With high accuracy, it can be used for numerous sample test in large-scale laboratories.

[Influence of dexamethasone on expression of 11beta-HSD2 in primary cultured cytotrophoblasts from human preterm placenta].

OBJECTIVE: To study the influence of dexamethasone (DEX) on the expression of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in primary cultured cytotrophoblasts from human preterm placenta. METHODS: Placenta villous cytotrophoblasts from preterm birth were cultured with the protocol of enzymatic dissociation and tissue incubation method. After isolation and identification, cytotrophoblasts were treated with the repeated administration of DEX (100 nmol/L), or DEX-RU486 (1 micromol/L) for 7 days, in which DEX was not added into the culture at 4th day. Cytotrophoblasts were collected everyday, and the expression levels of 11beta-HSD2 mRNA and protein were determined by real-time fluorescence quantitative PCR and Western blot method. RESULTS: After the treatment of DEX (100 nmol/L), the expression of 11beta-HSD2 mRNA and protein in cytotrophoblast increased in the first three days (P < 0.05). At 4th day, 11beta-HSD2 mRNA and protein declined in the absence of DEX. In 5th-7th day, the increase of 11beta-HSD2 expression were resumed when cytotrophoblasts received DEX again (P < 0.05). With the treatment of DEX and RU486 (l micromol/L), both mRNA and protein level of 11beta-HSD2 in cytotrophoblasts were lower than those with DEX alone, but there was not significantly different (P > 0.05). CONCLUSION: Repeated administration of DEX can upregulate the expression level of 11beta-HSD2 in primary cultured cytotrophoblasts from preterm placenta. Cytotrophoblasts from preterm birth may have the ability to protect the infants by the mechanism of 11beta-HSD2 regulation.

[Effect of N-acetylcysteine on lipopolysaccharide induced preterm labor in mice].

OBJECTIVE: To test the effect of N-acetylcysteine (NAC) on the mice with infection associated preterm labor. METHODS: The pregnant C57BL/6 mice were randomly distributed into five groups, each with 20 mice and were given lipopolysaccharide (LPS), saline solution (NS), NAC, LPS+NAC (therapy), and NAC+ LPS (prevention) respectively. The LPS (20 microg) was injected intraperitoneally to the mice every 12 hours since day 16 of gestation to induce preterm labor. The NAC was orally administered (0.5 g/kg) every 12 hours since day 15 or day 16 for the prevention and therapy groups respectively. The latency interval (from LPS injection to delivery of the first pup) and fetal survival rates were recorded in eight mice from each group. The remaining mice were killed at 4, 8, 12, and 24 hours after the LPS injection (three for a group each time). The NF-kappaB activity and IL-8 mRNA in uterine and maternal and fetal hepatic GSH-PX and serum IL-8, MDA, and SOD were examined. RESULTS: The average latency interval of LPS-treated mice was (15.1 +/- 1.9) hours, with a fetal survival rate of 4.3%. The NAC therapy extended the latency interval of LPS-treated mice to (35.4 +/- 2.1) hours, with a fetal survival rate of 69.0%. The NAC prevention extended the latency interval of LPS-treated mice to (44.8 +/- 2.6) hours, with a fetal survival rate of 84.3%. The expression of NF-KB P65 was activated and reached the peak 4 hours after the LPS injection. The uterine IL-8 mRNA and serum IL-8 and MDA reached the peak whereas the maternal and fetal hepatic GSH and SOD declined to the lowest 8 hours after the LPS injection. The NAC significantly inhibited the effect induced by the LPS (P < 0.01). CONCLUSION: The NAC has a therapeutic effect on the LPS-induced preterm labor in mice. It is even better to be used in preventing preterm labor. The mechanism of the protective effect of NAC may include the deactivation of the NF-kappaB/IL-8 and the reduce of the production of ROS.