A meta-analysis of the comparing of the first-generation and next-generation TKIs in the treatment of NSCLC.

Background: The current standard approach to the treatment of patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitizing mutations has been the treatment with a first-generation EGFR-TKIs. While, with resistance developed against first-generation EGFR-TKIs, second/third-generation TKIs have attracted all the attention, and replaced first-generation EGFR- TKIs upon disease progression due to the greater efficacy and more favorable tolerability. In the past few years, this strategy has been challenged by clinical evidence when next-generation EGFR-TKIs are used in patients with advanced NSCLC. Objective: In this study, we performed a meta- analysis to investigate the efficacy of next-generation TKIs comparison with first-generation TKIs in the treatment of NSCLC. Methods: The multiple databases including Pubmed, Embase, Cochrane library databases were adopted to search for the relevant studies, and full-text articles involving to comparison of next-generation TKIs and first-generation TKIs were reviewed. After rigorous reviewing on quality, the data was extracted from eligible randomized controlled trial (RCT). Meta-analysis Revman 5.3 software was used to analyze the combined pooled ORs with the corresponding 95% confidence interval using fixed- or random-effects models according to the heterogeneity. Results: A total of 5 randomized controlled trials were included in this analysis. The group of next-generation TKIs did achieved benefit in progression-free survival (PFS) (OR = 0.58, 95%CI = 0.45-0.75, P＜0.0001), overall survival (OS) (OR = 0.76, 95%CI = 0.65-0.90, P = 0.001) as well with the objective response rate (ORR) (OR = 1.27, 95%CI = 1.01-1.61, P = 0.04), respectively. In the results of subgroup analysis of PFS with EGFR mutations, there is also significant differences with exon 19 deletion (OR = 0.56, 95%CI = 0.41-0.77, P = 0.0003) and exon 21 (L858R) mutation (OR = 0.60, 95%CI = 0.49-0.75, P＜＝0.00001). While, the treatment-related severe adverse event (SAE) between the next-generation TKIs and first-generation TKIs did not have statistical significance (OR = 1.48, 95%CI = 0.62-3.55, P = 0.38). Conclusion: The next-generation TKIs significantly improved efficacy outcomes in the treatment of EGFR mutation-positive advanced NSCLC compared with the first-generation TKIs, with a manageable safety profile. These results are potentially important for clinical decision making for these patients.

Serum exosomal microRNA let-7i-3p as candidate diagnostic biomarker for Kawasaki disease patients with coronary artery aneurysm.

Kawasaki disease (KD) is a systemic vasculitis syndrome that leads to coronary artery aneurysm (CAA). While echocardiography is the most important imaging modality for coronary artery assessment, a specific diagnostic biomarker complementary for CAA has not been reported. We aimed to analyze the profiles of exosomal miRNAs extracted from the serum of KD patients and controls to identify candidate biomarkers for CAA. Serum samples from 39 healthy children, 42 CAA patients, 38 coronary artery dilatation (CAD) patients and 45 virus-infected patients including 24 EBV patients and 21 ADV patients were randomly selected. Next generation sequencing was used to analyze serum exosomal miRNA to detect differentially expressed miRNAs. Biomarker candidates were validated by qRT-PCR. One hundred (and) ninety-six differentially expressed miRNAs (DEMs) were detected in CAA patients and healthy children. There were 70 DEMs and 140 DEMs in CAA patients versus CAD patients, and in CAA patients versus virus-infected patients, respectively. We selected the three most upregulated (let-7i-3p, miR-17-3p, and miR-210-5p) and the three most downregulated miRNAs (miR-6743-5p, miR-1246, and miR-6834-5p) in the DEMs, which were expressed differentially in CAA patients versus healthy children, and in CAA patients versus virus-infected patients, not in virus-infected patients versus healthy children, as biomarker candidates. Excluded DEMs of CAD and virus-infected patients, let-7i-3p was detected by sequence data analysis as a biomarker candidate for CAA patients, and then validated by qRT-PCR in a larger set of clinical samples. As a biomarker candidate, let-7i-3p provides an additional means of diagnosing CAA patients. Additionally, miRNA biomarkers complement ultrasonic imaging, allowing for greater diagnostic precision. © 2019 IUBMB Life, 2019.

Proteomics study of serum exosomes in Kawasaki disease patients with coronary artery aneurysms.

BACKGROUND: To study the protein profile of the serum exosomes of patients with coronary artery aneurysms (CAA) caused by Kawasaki disease (KD). METHODS: Two-dimensional electrophoresis (2-DE) was used to identify proteins from the exosomes of serum obtained from children with CAA caused by KD, as well as healthy controls. Differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight/timeof-flight mass spectrometry (MALDI-TOF/TOF MS) analysis. RESULTS: Thirty two differentially expressed proteins were identified (18 up-regulated and 14 downregulated) from serum exosomes of children with CAA and were compared to healthy controls. The expression levels of 4 proteins (TN, RBP4, LRG1, and APOA4) were validated using Western blotting. Classification analysis and protein-protein network analysis showed that they are associated with multiple functional groups, including host immune response, inflammation, apoptotic process, developmental process, and biological adhesion process. CONCLUSIONS: These findings establish a comprehensive proteomic profile of serum exosomes from children with CAA caused by KD, and provide additional insights into the mechanisms of CAA caused by KD.

Serum α-1 Acid Glycoprotein is a Biomarker for the Prediction of Targeted Therapy Resistance in Advanced EGFR-positive Lung Adenocarcinoma.

OBJECTIVE: To determine the levels of α-1 acid glycoprotein (ORM1) in the sera of advanced lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutation before treatment and after acquirement of EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance, and to explore the clinical cut off value of ORM1 for targeted therapy resistance in LUAD. METHODS: Enzyme-linked immunosorbent assay was used to determine serum ORM1 levels. Receiver operating characteristic curve was applied to evaluate the serum ORM1 level in the resistance of EGFR-TKI and the cut off value of ORM1 for the diagnosis of EGFR-TKI resistance. RESULTS: The serum ORM1 concentrations in the healthy group, before and after drug resistance were 1.687 ± 0.103, 1.868 ± 0.101, and 1.731 ± 0.088 µg/ml, respectively. The serum ORM1 concentrations before and after drug resistance were higher than that of the healthy group, whereas the serum ORM1 concentrations in the resistant group were lower than those before drug treatment. In comparison to healthy group, the area under curve (AUC) of the serum ORM1 concentration was 0.918 ± 0.029 with sensitivity of 90.5% and specificity of 78.6% in the patient before EGFR-TKI treatment, while the AUC was 0.644 ± 0.062 with sensitivity of 69.0% and specificity of 66.7% in the resistance group. When compared to those before treatment, the AUC of serum ORM1 concentration was 0.880 ± 0.038 with a sensitivity of 92.9% and specificity of 73.8% in the resistance group. The cutoff value of serum ORM1 was 1.778 µg/ml for advanced EGFR-positive LUAD and 1.723 µg/ml after resistance to EGFR-TKI. CONCLUSION: Serum ORM1 has an important diagnostic value for the diagnosis of EGFR-positive LUAD and EGFR-TKI resistance in patients especially with advanced EGFR-positive LUAD. Our findings suggest that serum ORM1 is a biomarker in the prediction of EGFR-TKI resistance in EGFR-positive LUAD.

Sets of serum exosomal microRNAs as candidate diagnostic biomarkers for Kawasaki disease.

Although Kawasaki disease is the main cause of acquired heart disease in children, no diagnostic biomarkers are available. We aimed to identify candidate biomarkers for diagnosing Kawasaki disease using serum exosomal microRNAs (miRNAs). Using frozen serum samples from a biobank, high-throughput microarray technologies, two-stage real-time quantitative PCR, and a self-referencing strategy for data normalization, we narrowed down the list of biomarker candidates to a set of 4 miRNAs. We further validated the diagnostic capabilities of the identified miRNAs (namely, CT(miR-1246)-CT(miR-4436b-5p) and CT(miR-197-3p)-CT(miR-671-5p)) in 79 samples from two hospitals. We found that this 4-miRNA set could distinguish KD patients from other febrile patients as well as from healthy individuals in a single pass, with a minimal rate of false positives and negatives. We thus propose, for the first time, that serum exosomal miRNAs represent candidate diagnostic biomarkers for Kawasaki disease. Additionally, we describe an effective strategy of screening for biomarkers of complex diseases even when little mechanistic knowledge is available.

Proteomic analysis associated with coronary artery dilatation caused by Kawasaki disease using serum exosomes.

INTRODUCTION: The aim of this study was to investigate the serum exosome proteome profile of coronary artery dilatation (CAD) caused by Kawasaki disease (KD). METHODS: Two-dimensional electrophoresis was implemented on proteins of serum exosomes obtained from children with CAD caused by KD and from healthy controls. Differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry analysis. RESULTS: We identified 38 differentially expressed proteins (13 up-regulated and 25 down-regulated) from serum exosomes of patients with CAD caused by KD compared with healthy controls. Expression levels of three differentially expressed proteins (leucine-rich alpha-2-glycoprotein, sex hormone-binding globulin, and serotransferrin) were validated using western blot analysis. Classification and protein-protein network analysis showed that they are associated with multiple functional groups involved in the acute inflammatory response, defense response, complement activation, humoral immune response, and response to wounding. The majority of the proteins are involved in the inflammation and coagulation cascades. CONCLUSIONS: These findings establish a comprehensive proteome profile of CAD caused by KD and increase our knowledge of scientific insight into its mechanisms.

Study on Chinese medicine syndrome of colorectal carcinoma in perioperative period.

OBJECTIVE: To explore the distribution characteristics of Chinese medicine (CM) syndromes and the rule of dynamic evolvement in patients with colorectal cancer at the perioperative period by applying a mathematical statistics methodology. METHODS: By using the overall sample date, and cross-sectional descriptive and prospective researching methods, the clinical data of CM symptoms of patients with colorectal cancer from the first day of preoperative care to the third, seventh, and tenth days after the operation were collected. The distribution characteristics of CM syndromes and dynamic evolution were concluded upon by experts, and then by building up a database through the use of EpiData3.1 the frequency statistics and cluster analyses were applied utilizing SAS9.2 software. RESULTS: Among 210 cases of patient, on the day before the operation, the main route of syndrome was blood deficiency (33.33%), followed by the syndrome of deficiency of both qi and yin (28.57%). On the third day after surgery, the main syndrome was qi deficiency (47.62%), followed by yin deficiency inner-heat. On the seventh day after surgery, the main syndrome was both yin deficiency inner-heat (33.33%) and phlegm-dampness (33.33%). On the tenth day after surgery, the main syndrome was a deficiency of both qi and yin (38.09%), followed by dampness and hot accumulative knotting (33.33%). CONCLUSION: Research in the field of the distribution characteristics of CM syndromes and dynamic evolution will provide an objective basis for syndrome differentiation for patients in the perioperative period, further advancing the study of preventing and decreasing relapse and metastasis in CM therapy.

MicroRNA expression profile in exosome discriminates extremely severe infections from mild infections for hand, foot and mouth disease.

BACKGROUND: Changes of miRNAs in exosome have been reported in different disease diagnosis and provided as potential biomarkers. In this study, we compared microRNA profile in exosomes in 5 MHFMD and 5 ESHFMD as well as in 5 healthy children. METHODS: Different expression of miRNAs in exosomes across all the three groups were screened using miRNA microarray method. Further validated test was conducted through quantitative real-time PCR assays with 54 exosome samples (18 ESHFMD, 18 MHFMD, and 18 healthy control). The judgment accuracy was then estimated by the receiver operating characteristic (ROC) curve analysis; and the specificity and sensitivity were evaluated by the multiple logistic regression analysis. RESULTS: There were 11 different miRNAs in exosomes of MHFMD and ESHFMD compared to healthy children, of which 4 were up-regulated and 7 were down-regulated. Further validation indicated that the 4 significant differentially expressed candidate miRNAs (miR-671-5p, miR-16-5p, miR-150-3p, and miR-4281) in exosome showed the same changes as in the microarray analysis, and the expression level of three miRNAs (miR-671-5p, miR-16-5p, and miR-150-3p) were significantly different between MHFMD or ESHFMD and the healthy controls. The accuracy of the test results were high with the under curve (AUC) value range from 0.79 to 1.00. They also provided a specificity of 72%-100% and a sensitivity of 78%-100%, which possessed ability to discriminate ESHFMD from MHFMD with the AUC value of 0.76-0.82. CONCLUSIONS: This study indicated that the exosomal miRNA from patients with different condition of HFMD express unique miRNA profiles. Exosomal miRNA expression profiles may provide supplemental biomarkers for diagnosing and subtyping HFMD infections.

Monitoring of the serum proteome in Kawasaki disease patients before and after immunoglobulin therapy.

Kawasaki disease (KD) is a systemic vasculitis that mainly affects children younger than 5 years. The causal pathogen is unknown, therefore specific diagnostic biomarkers and therapy are unavailable. High-dose intravenous immunoglobulin (IVIG) is considered as the most effective therapy to reduce the prevalence of coronary artery lesion (CAL) in KD; however, it has side effects. This study aimed to (1) determine whether IVIG therapy is effective at the molecular level; (2) provide the first serum proteomic profile of KD under IVIG therapy; and (3) screen for monitoring biomarker candidates. We extracted serum proteins from samples of healthy individuals and from KD patients before and after IVIG therapy, and employed two-dimensional electrophoresis and MALDI-TOF/TOF mass spectrometry to identify differentially expressed proteins. The identifications were validated by Western blotting. We identified 29 differentially expressed proteins in KD patients and found that IVIG therapy restored most of these proteins to near-normal levels. Tracing the protein levels of single patients before and after IVIG therapy showed that the proteins, especially Transthyretin (TTR), are potential markers for therapeutic monitoring. Functional analyses of these proteins by PANTHER and String suggested that the key influence of KD lay in the immune system, which was targeted by IVIG.

Proteomic analysis of extremely severe hand, foot and mouth disease infected by enterovirus 71.

BACKGROUND: To clarify the molecular mechanisms that participate in the severe hand, foot and mouth disease (HFMD) infected by Enterovirus 71 and to detect any related protein biomarkers, we performed proteomic analysis of protein extracts from 5 extremely severe HFMD children and 5 healthy children. METHODS: The protein profiles of them were compared using two-dimensional electrophoresis. Differentially expressed proteins were identified using mass spectrometry. Functional classifications of these proteins were based on the PANTHER. The interaction network of the differentially expressed protein was generated with Pathway Studio. RESULTS: A total of 38 differentially expressed proteins were identified. Functional classifications of these proteins indicated a series of altered cellular processes as a consequence of the severe HFMD. These results provided not only new insights into the pathogenesis of severe HFMD, but also implications of potential therapeutic designs. CONCLUSIONS: Our results suggested the possible pathways that could be the potential targets for novel therapy: viral protection, complement system and peroxide elimination.