The Impact of Modified Body Mass Index on Clinical Prognosis in the Elderly With Acute Ischemic Stroke.

OBJECTIVES: The modified body mass index (mBMI) combines the body mass index and serum albumin, accurately reflecting the nutritional status. It remains uncertain whether modified body mass index influences neurological function and clinical prognosis in elderly patients with acute ischemic stroke. METHODS: We divided the cohort into quartiles of mBMI (1 to 4). The primary outcome was analyzed using the percentage of patients with a 90-day modified Rankin scale (mRS) score of 0 to 1. There were 7 secondary outcomes, including the disability level at 90 days and the National Institute of Health Stroke Scale (NIHSS) score at 14 and 90 days. RESULTS: mBMI was negatively associated with clinical prognosis at 90-day mRS score in the primary outcome (ß=-0.167; 95% CI -0.311 to 0.023, P=0.023). Moreover, mBMI1 (<896.72) and primary outcomes (ß=0.438; 95% CI: -0.018 to 0.894) were positively correlated with higher mBMI. Moreover, the number and percentage of patients completing all the duties and activities are also higher. Age-adjusted Charlson comorbidity index (aCCI) and posterior circulation lesion were positively associated with the clinical prognosis 90-day mRS score in the primary outcome (ß=2.218; 95% CI: 1.144-4.300, ß=2.771; 95% CI: 1.700-4.516). However, BMI and serum albumin were not associated the with clinical prognosis primary outcome. BMI negatively correlates with secondary outcomes (NIHSS at discharge, ß=-0.023; 95% CI: -0.102 to 0.057). CONCLUSIONS: Our study revealed that mBMI and not BMI could be a better primary outcome predictor in the elderly with acute ischemic stroke, and lower mBMI showed a worse prognosis.

The impact of whole-body vibration training and proprioceptive neuromuscular facilitation on biomechanical characteristics of lower extremity during cutting movement in individuals with functional ankle instability: A parallel-group study.

BACKGROUND: We compared the effects of whole-body vibration training and proprioceptive neuromuscular facilitation on the biomechanical characteristics of the lower limbs in functional ankle instability patients during cutting movement to ascertain the superior rehabilitation method. METHODS: Twenty-two male College students with unilateral functional ankle instability volunteered for this study and were randomly divided into whole-body vibration training group and proprioceptive neuromuscular facilitation group. Kinematics data and ground reaction forces were collected using infrared motion capture system and 3-D force plates synchronously during cutting. Repeated measures two-way ANOVA was performed to analyze the data. FINDINGS: Both training methods reduced the maximum hip abduction angle (p = 0.010, effect size: proprioceptive neuromuscular facilitation = 0.69; whole-body vibration training = 0.20), maximum knee flexion angle (p = 0.008, effect size: proprioceptive neuromuscular facilitation = 0.39, whole-body vibration training = 1.26) and angular velocity (p = 0.014, effect size: proprioceptive neuromuscular facilitation = 0.62, whole-body vibration training = 0.55), maximum ankle inversion angular velocity (p = 0.020, effect size: proprioceptive neuromuscular facilitation = 0.52, whole-body vibration training = 0.81), and knee flexion angle at the time of maximum vertical ground reaction forces (p = 0.018, effect size: proprioceptive neuromuscular facilitation = 0.27, whole-body vibration training = 0.76), and increased the maximum ankle dorsiflexion moment (p = 0.049, effect size: proprioceptive neuromuscular facilitation = -0.52, whole-body vibration training = -0.22). Whole-body vibration training reduced the maximum ground reaction forces value in the mediolateral directions (p = 0.010, effect size = 0.82) during cutting movement. INTERPRETATION: These findings suggested that the two types of training might increase neuromuscular conduction function around the ankle. After these two types of training, functional ankle instability patients showed a similar risk of injury to the lateral ankle ligaments during cutting.

Exosomes derived from M1 macrophages inhibit the proliferation of the A549 and H1299 lung cancer cell lines via the miRNA-let-7b-5p-GNG5 axis.

Background: Almost all cells are capable of secreting exosomes (Exos) for intercellular communication and regulation. Therefore, Exos can be used as a natural therapeutic platform to regulate genes or deliver drugs to treat diseases. M1 macrophages inhibit tumor growth by releasing pro-inflammatory factors. This study explored the applicability of M1 macrophage exosomes (M1-Exos) as gene carriers and the effects on GNG5 protein, and further examined whether macrophage repolarization could inhibit tumor activity. Methods: M0 macrophages were polarized toward M1 using vitexin. Exos were obtained from M1 macrophages by ultra-centrifugation. The transwell non-contact co-culture system was used to co-culture M1 macrophages with HLF-α human lung epithelial cells or A549 or H1299 lung cancer cells. MTT, scratch, and transwell assays were used to detect the cell viability, migration, and invasion ability of cells in the four groups. Flow cytometry was used to detect the apoptosis rate of each group, and western blot (WB) analysis was performed to detect the change in the expression of proliferation- and apoptosis-related proteins. We screened the differentially expressed microRNAs using quantitative polymerase chain reaction technology. Luciferase reporter analysis was performed to explore the interaction between miRNA and protein. We used Xenografted A549 tumors in nude mice to study the effect of M1-Exos on tumor cell growth in vivo. Results: The results showed that, under the M1 macrophage co-culture system, lung cancer cell viability, invasion, and migration ability decreased, and the number of apoptotic cells increased, will all indicators being statistically significant (P < 0.05). The expression levels of PCNA, KI67, and Bcl-2 decreased significantly, but that of Bax increased (P < 0.05). Exosomes can have the same effect on tumor cells as M1 macrophages. Exosomes can transport miR-let-7b-5p to tumor cells, and miR-let-7b-5p can inhibit tumor cell proliferation and promote tumor cell apoptosis by regulating the GNG5 protein level. Conclusions: M1-Exos inhibit the proliferation, invasion, and metastasis of lung cancer cells through miRNA-let-7b-5p and GNG5 signaling pathways and inhibit the anti-apoptotic ability of lung cancer cells.

Mental health of junior college students in China during COVID-19 school lockdown: Findings of on-line cross-sectional survey.

During the COVID-19 pandemic, junior students who had recently entered university may have experienced particular difficulties. This study aimed to investigate the incidence of anxiety, depression, and sleep status among junior college students during school closure. Junior college students from 3colleges in Anhui Province participated in this study from 6th to 20th April, 2022. The students' data were collected using a designed online questionnaire developed on the "Wen juan xing" website and submitted via cell phone. Ordinal logistic regression analysis indicated that female sex was an independent risk factor for increased anxiety, depression, and insomnia (anxiety: OR 1.503, 95% CI 1.191-1.897; depression: OR 1.14, 95% CI 1.023-1.270; ISI OR 2.052, 95% CI 1.646-2.559). Notably, medical specialty was an independent risk factor for depression and anxiety (anxiety: OR 1.367, 95% CI 1.078-1.734; depression: OR 1.289, 95% CI 1.148-1.448). Moreover, being a freshman was a risk factor for increased depression and insomnia (depression: OR 1.036,95% CI 0.931-1.153; insomnia: (OR 1.157,95% CI 0.961-1.394). The findings indicate that a considerable portion of junior college students experienced psychological problems due to lockdowns during the COVID-19 pandemic.

[Transcriptomics analysis of key genes and signaling pathways in sepsis-related exogenous acute respiratory distress syndrome].

OBJECTIVE: To analyze the differentially expressed gene (DEG) in rats with sepsis-induced exogenous acute respiratory distress syndrome (ARDS) and explore the early diagnosis and protective mechanism of sepsis-induced ARDS at the transcriptome level. METHODS: Twelve 6 to 8 weeks old male Sprague-Dawley (SD) rats were randomly divided into lipopolysaccharide (LPS) induced sepsis-induced ARDS model group (model group, intraperitoneal injection of LPS 15 mg/kg) and control group (intraperitoneal injection of the same volume of normal saline), with 6 rats in each group. RNA was extracted from the left lung tissue of the two groups, and the paired-end sequencing mode of the illumina Hiseq sequencing platform was used for high-throughput sequencing. The DESeq2 software was used to screen DEG with |log2 (fold change, FC)| ≥ 3 and P < 0.001. Gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on DEG. STRING and CytoScape software were used to construct a protein-protein interaction (PPI) network and screen key genes. The peripheral blood mononuclear cell (PBMC) of 20 septic patients admitted to the emergency and critical care medical department of Lianyungang First People's Hospital from March to November 2021 and 20 age-matched healthy people in the same period were isolated and extracted, and the key genes were verified by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). RESULTS: A total of 286 DEG were screened, including 202 up-regulated genes and 84 down-regulated genes. GO enrichment analysis showed that DEG was mainly involved in biological processes such as neutrophil chemotaxis migration, antibacterial humoral response, host immune response, and humoral immune response. KEGG analysis showed that DEG mainly played a biological role through interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and chemokine signaling pathway. In PPI analysis, a total of 262 node proteins were screened, and the interaction relationship was 852 edges. The first 15 key genes were IL-6, TNF, IL-10, IL-1ß, chemokine ligand 1 (CXCL1), CXCL10, chemokine receptor 3 (CXCR3), CXCR2, CXCL9, chemokine ligand 7 (CCL7), CXCL11, CCL1, CXCL13, CCL12, and CCL22. Five representative key genes were performed on PBMC of blood samples from septic ARDS patients and healthy controls by RT-qPCR. The results showed that their expression was significantly higher than that in the healthy controls [IL-6 mRNA (2-ΔΔCt): 2.803±1.081 vs. 0.951±0.359, TNF mRNA (2-ΔΔCt): 2.376±0.799 vs. 1.150±0.504, CXCL10 mRNA (2-ΔΔCt): 2.500±0.815 vs. 1.107±0.515, CXCR3 mRNA (2-ΔΔCt): 1.655±0.628 vs. 0.720±0.388, CCL22 mRNA (2-ΔΔCt): 1.804±0.878 vs. 1.010±0.850, all P < 0.05], and the trends were consistent with the RNA-Seq results. CONCLUSIONS: Biological processes such as chemotactic migration and degranulation of inflammatory cells, cytokine immune response, and signal pathways such as CXCL10/CXCR3 and IL-17 play important roles in the occurrence and development of sepsis-related exogenous ARDS, which would provide new ideas and targets for further study of lung injury mechanisms and clinical prevention and treatment.

Whole Transcriptomic Analysis of Key Genes and Signaling Pathways in Endogenous ARDS.

Objective: To analyze the differentially expressed genes (DEGs) in rats with endogenous acute respiratory distress syndrome (ARDS) lung injury and explore the pathogenesis and early diagnostic molecular markers using whole transcriptomic data. Methods: Twelve 8-week-old male Sprague Dawley rats were selected and randomly and equally divided into ARDS lung injury group and normal control group. RNA was extracted from the left lung tissues of both the groups and sequenced using the paired-end sequencing mode of the Illumina Hiseq sequencing platform. The DEGs of miRNA, cirRNA, lncRNA, and mRNA were screened using DESeq2 software, and the ceRNA regulatory network was constructed using Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the mRNA DEGs. STRING and Cytoscape software were used to construct the protein interaction network and identify the 15 key genes, which were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Results: Based on different screening conditions, and compared with the control group, the ARDS lung injury group showed 836 mRNA DEGs (386 upregulated and 450 downregulated), 110 lncRNA DEGs (53 upregulated and 57 downregulated), 19 circRNA DEGs (3 upregulated and 16 downregulated), and 6 miRNA DEGs (5 upregulated and 1 downregulated gene). GO showed that the DEGs of mRNA were mainly involved in biological processes, such as defense response to lipopolysaccharide and other organisms, leukocyte chemotaxis, neutrophil chemotaxis, and cytokine-mediated signaling. KEGG enrichment analysis showed that the DEGs played their biological roles mainly by participating in IL-17, TNF, and chemokine signaling pathways. The PPI analysis showed a total of 281 node proteins and 634 interaction edges. The top 15 key genes, which were screened, included Cxcl10, Mx1, Irf7, Isg15, Ifit3, Ifit2, Rsad2, Ifi47, Oasl, Dhx58, Usp18, Cmpk2, Herc6, Ifit1, and Gbp4. The ceRNA network analysis showed 69 nodes and 73 correlation pairs, where the key gene nodes were miR-21-3p, Camk2g, and Stx2. Conclusions: The chemotaxis, migration, and degranulation of inflammatory cells, cytokine immune response, autophagy, and apoptosis have significant biological functions in the occurrence and development of endogenous acute lung injury during ARDS. Thus, the camk2g/miR-21-3p/lncRNA/circRNA network, CXCL10/CXCR3, and IL-17 signaling pathways might provide novel insights and targets for further studying the lung injury mechanism and clinical treatment.

Identification and validation of autophagy-related genes in exogenous sepsis-induced acute respiratory distress syndrome.

OBJECTIVE: To analyze the differential expression of autophagy-related genes of sepsis-induced acute respiratory distress syndrome (ARDS) as potential markers for early diagnosis. METHODS: Male Sprague-Dawley rats (aged 8 weeks) were selected and randomly divided into sepsis-induced ARDS group (n = 6) and a normal control group (n = 6). Lung tissue samples were collected for high-throughput sequencing using Illumina HiSeq sequencing platform in the paired-end sequencing mode. Differentially expressed genes (DEGs) were screened by DESeq. 2 software [|log2FC | ≥1 and p < .05] and autophagy-related genes were identified using Mouse Genome Informatics. Co-expressed autophagy-related DEGs from these two datasets were filtered by construction of a Venn diagram. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these autophagy-related DEGs and a protein interaction network was constructed using STRING and Cytoscape software to identify hub genes, which were verified by real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: A total of 42 autophagy-related DEGs (26 upregulated genes and 16 downregulated genes) were identified. The GO and KEGG pathway analyses showed enrichment in 969 biological processes (BPs), three cellular components (CCs), eight molecular functions (MFs) and 27 signaling pathways. The protein interaction (PPI) network revealed 42 node proteins and 75 interacting edges, with an average node degree of 3.52, and an average local clustering coefficient of 0.509. Among the top 10 hub genes with the RNA-Seq, six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) were validated by qRT-PCR (all p < .05). CONCLUSION: 42 potential autophagy-related genes associated with sepsis-induced ARDS lung injury were identified and six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) may affect the development of ARDS by regulating autophagy. These results expanded our understanding of ARDS and might be useful in treatment of exogenous sepsis-induced ARDS.

Detection of an EML4-ALK fusion mutation secondary to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer: a case report.

BACKGROUND: For epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine inhibitors such as gefitinib, erlotinib, and osimertinib, are recommended as the preferred first-line treatment. Unfortunately, relevant drug resistance is often inevitable and for first and second generation EGFR-tyrosine kinase inhibitors (TKIs), drug resistance most commonly (50-60% of cases) occurs at the secondary point mutation T790M. Second-line treatments may include administering the third generation of EGFR-TKIs, such as osimertinib and almonertinib. In a few relevant studies, rearrangement of the anaplastic lymphoma kinase (ALK) gene was detected in patients with T790M mutation after drug resistance to osimertinib re-occurred following administration as a second-line treatment. The studies concluded that ALK rearrangement is a rare but critical drug resistance mechanism for osimertinib. However, to date, it remains unclear whether almonertinib also triggers the same ALK rearrangement. The current case study is the first one detailing the detection of an ALK rearrangement after almonertinib resistance in advanced EGFR-mutant NSCLC, which contributes to the limited body of literature examining ALK rearrangement as a mechanism of resistance to EGFR-TKIs in advanced EGFR-mutant NSCLC. CASE DESCRIPTION: Herein, we present a 35-year-old female patient with EGFR-mutant advanced NSCLC in the last trimester of pregnancy. The patient was administered multiple treatments, including first-line icotinib and second-line almonertinib. According to the next-generation sequencing (NGS) assay after almonertinib resistance, the development of an EML4-ALK fusion mutation was considered to be a potential mechanism of almonertinib resistance. Subsequently, the patient received a combination of almonertinib and crizotinib, and at the last follow-up, the treatment showed a curative effect and then maintained a one-month stable disease. CONCLUSIONS: This case report suggests that ALK rearrangement may be a potential mechanism of almonertinib resistance. The combination of ALK TKI therapy and EGFR TKI may be a viable strategy for almonertinib-resistant NSCLC patients induced by ALK rearrangement.

A systematic review and meta-analysis of circulating cell-free DNA as a diagnostic biomarker for non-small cell lung cancer.

Background: Early diagnosis of non-small cell lung cancer (NSCLC) is crucial for treatment. Circulating cell-free DNA (cfDNA) is an extracellular nucleic acid found in serum, and tumor cfDNA circulating in the blood may be used as a biomarker for early diagnosis. The purpose of this study was to evaluate the application value of cfDNA as a biomarker for the diagnosis of NSCLC through meta-analysis. Methods: We searched the China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases using the following search terms: lung cancer, NSCLC, biomarkers, circulating cfDNA, cfDNA, circulating tumor DNA (ctDNA), circulating cell-free tumor DNA, and diagnosis. The retrieval period was set until September 2021. According to PICOS (patients, intervention, comparison, outcomes, and study design) principles the inclusion criteria were: aged ≥18 years; at least 10 NSCLC cases; NSCLC patients diagnosed by histopathology or cytology; circulating cfDNA was detected; outcome data could be completely extracted. Bias risk assessment was conducted according to the QUADAS (Quality Assessment of Diagnostic Accuracy Studies). RevMan 5.3 was used for meta-analysis. Results: Eight studies met the inclusion criteria, including a total of 618 NSCLC patients and 635 healthy subjects. The overall sensitivity and specificity were 0.79 [95% confidence interval (CI): 0.75-0.82] and 0.81 (95% CI: 0.78-0.84), respectively. The area under the curve (AUC) of the summary receiving operating characteristic (SROC) curve was 0.8941. The pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio were 5.37 (95% CI: 2.67-10.81), 0.24 (95% CI: 0.15-0.38), and 24.68 (95% CI: 8.85-68.84), respectively. The patient selection bias was high in two articles was high, unclear in one article, and low in the remaining five ones. The risk of bias in the research index test was unclear in one article, and low in the remaining seven articles. The reference standard bias, and flow and time bias of all articles was low. Conclusions: Circulating cfDNA is an efficacy biomarker in diagnosis of NSCLC. Its clinical application technology is worthy of further research.

Special type of Wernekink syndrome in midbrain infarction: Four case reports.

BACKGROUND: Wernekink commissural syndrome (WCS) is a distinct midbrain syndrome that involves the caudal tegmentum of the midbrain and selectively damages the Wernekink commissure involved in the decussation of the superior cerebellar peduncle in midbrain. The aim of the study was to explore the clinical manifestations, imaging characteristics, and differential diagnosis of WCS in midbrain infarction to provide reference for clinicians in the diagnosis of WCS. CASE SUMMARY: The clinical data of 4 patients with WCS with midbrain infarction were analyzed retrospectively. WCS is a rare syndrome that can be diagnosed based on its characteristic symptoms and imaging findings of magnetic resonance imaging. CONCLUSION: Clinicians should look for this syndrome in cases of bilateral cerebellar dysfunction and eye movement disorders.

Efficacy and Safety of Gefitinib Plus Anlotinib for Patients with EGFR Positive Advanced Non-Small-Cell Lung Cancer: A Retrospective Exploratory Study.

Objective: This study was to investigate the efficacy and safety of gefitinib plus anlotinib for patients with EGFR positive advanced non-small cell lung cancer (NSCLC) in a first-line setting. Methods: A total of 36 patients with previously-untreated EGFR positive advanced NSCLC were included in this study retrospectively. All patients were administered with gefitinib plus anlotinib combination therapy. The efficacy of the patients was evaluated with the change of target lesion using imaging evidence according to RECIST 1.1 criteria and all the patients were followed up regularly. Adverse reactions were collected and documented during the combination administration. Univariate analysis according to the baseline characteristic subgroup was implemented using Log rank test and multivariate analysis was adjusted by Cox regression analysis. Results: All the 36 patients included in our study were available for efficacy and safety analysis. Best overall response of the patients during gefitinib plus anlotinib administration suggested that partial response was observed in 30 patients, stable disease was noted in five patients, and progressive disease was found in one patient, which yielded an objective response rate (ORR) of 83.3% (95% CI=67.2-93.6%) and a disease control rate (DCR) of 97.2% (95% CI=85.5-99.9%). Prognostic data indicated that the median progression-free survival (PFS) of the 36 patients with NSCLC was 15.2 months (95% CI=8.15-22.26). Furthermore, the median overall survival (OS) of the 36 patients was 35.9 months (95% CI=22.77-49.03). Additionally, the most common adverse reactions of the patients with NSCLC were diarrhea (63.9%), fatigue (58.3%), hypertension (50.0%), rash (44.4%), and nausea and vomiting (41.7%). Furthermore, ECOG performance status was associated with PFS of gefitinib plus anlotinib combination therapy in baseline characteristic subgroup analysis. Conclusion: Gefitinib plus anlotinib regimen demonstrated encouraging efficacy and an acceptable safety profile for patients with previously untreated EGFR positive NSCLC preliminarily. The conclusion should be validated in prospective clinical trials subsequently.

Recent Progress in Active Mechanical Metamaterials and Construction Principles.

Active mechanical metamaterials (AMMs) (or smart mechanical metamaterials) that combine the configurations of mechanical metamaterials and the active control of stimuli-responsive materials have been widely investigated in recent decades. The elaborate artificial microstructures of mechanical metamaterials and the stimulus response characteristics of smart materials both contribute to AMMs, making them achieve excellent properties beyond the conventional metamaterials. The micro and macro structures of the AMMs are designed based on structural construction principles such as, phase transition, strain mismatch, and mechanical instability. Considering the controllability and efficiency of the stimuli-responsive materials, physical fields such as, the temperature, chemicals, light, electric current, magnetic field, and pressure have been adopted as the external stimuli in practice. In this paper, the frontier works and the latest progress in AMMs from the aspects of the mechanics and materials are reviewed. The functions and engineering applications of the AMMs are also discussed. Finally, existing issues and future perspectives in this field are briefly described. This review is expected to provide the basis and inspiration for the follow-up research on AMMs.

Electrochemically promoted oxidative α-cyanation of tertiary and secondary amines using cheap AIBN.

The electrochemical α-cyanation of tertiary and secondary amines has been developed by using a cheap cyanide reagent, azobisisobutyronitrile (AIBN). The CN radical, generated through n-Bu4NBr-meidated electrochemical oxidation, participates in a novel α-cyanation reaction under exogenous oxidant-free conditions.

Association Between PDL1 Genetic Variation and Efficacy of Apatinib Monotherapy in Patients with Previously Treated Advanced NSCLC: A Real-World Retrospective Study.

BACKGROUND: This study aimed to explore associations between PDL1 polymorphisms and efficacy of apatinib for patients with previously treated advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: We retrospectively recruited 148 patients with previously treated advanced NSCLC from January 2015 to December 2019 continuously. Clinical efficacy in patients receiving apatinib treatment was evaluated. Adverse reactions were documented during treatment. Biological specimens of peripheral blood and cancer tissue biopsies were obtained for the genotyping of genetic variations in PDL1 and corresponding gene-mRNA expression, respectively. Univariate association analysis between the status of PDL1 genetic variations and survival was performed with Kaplan-Meier survival analysis. RESULTS: The objective response rate of the 148 patients was 17.6% and disease-control rate 68.9%. Prognostic data suggested that median progression-free survival (PFS) was 3.8 (95% CI 3.13-4.47) months and median overall survival (OS) 10.5 (95% CI 9.06-11.95) months. Regarding PDL1 genetic variation, only rs2297136 was of clinical significance. Prognosis analysis revealed that PFS and OS for the rs2297136 genotype were significantly different. Median PFS of patients with TC/CC and TT genotypes was 3 and 4.5 months, respectively (P=0.006). Median OS of the two genotypes was 9 and 11.6 months, respectively (P=0.04). Furthermore, the safety profile suggested that the most common adverse reactions were hypertension, dermal toxicity, fatigue, and oral toxicity. This study failed to find any significant association between adverse reactions and rs2297136. Interestingly, mRNA-expression analysis demonstrated that mRNA expression of PDL1 in biopsy cancer-tissue specimens was significantly different based on rs2297136-genotype status (P<0.001). CONCLUSION: The PDL1 polymorphism rs2297136 could be used as a potential biomarker for the prognosis of patients with NSCLC receiving apatinib monotherapy.

The Influence of KDR Genetic Variation on the Efficacy and Safety of Patients With Advanced NSCLC Receiving First-Line Bevacizumab Plus Chemotherapy Regimen.

OBJECTIVE: Angiogenesis plays an important role in the growth and metastasis of non-small cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody that mainly acts on vascular endothelial growth factor A (VEGFA). Kinase insert domain receptor (KDR) is the most important target of VEGFA. The aim of present study was to investigate the influence of KDR genetic variation on the efficacy and safety of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimen. METHODS: A total of 169 patients with advanced NSCLC who received bevacizumab combined with chemotherapy were recruited in this study. Clinical outcome of the regimens was evaluated in the hospital. Peripheral blood and biopsy tissue specimens of patients were collected for the genotyping of KDR genetic variation and KDR mRNA expression, respectively. The association between KDR genotype status and other variables were analyzed. Univariate analysis of genotype status and prognosis was implemented using the Kaplan-Meier survival analysis method. Multivariate Cox regression analysis was performed to adjust the confounding factors. RESULTS: Of the polymorphisms analyzed, only V297 L was of clinical significance. The prevalence of V297 L among the study population were as follows: CC genotype 123 cases (72.8%), CT genotype 41 cases (24.3%), TT genotype 5 cases (2.9%). The minimum allele frequency is 0.15. The distribution frequencies of the 3 genotypes corresponded with Hardy-Weinberg equilibrium (P = 0.489). Patients with TT and CT genotypes were merged in the subsequent comparison of clinical outcomes. The analysis of efficacy exhibited that the objective response rates (ORR) of patients with CC genotype and CT/TT genotypes were 52.8% and 47.8% (P = 0.561), respectively. Prognosis indicated that the median progression free survival (PFS) of patients with CC genotype and CT/TT genotype were 8.9 and 5.5 months, respectively (P = 0.006). The median OS of the 2 genotypes were 20.0 and 14.9 months, respectively (P = 0.021). Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS [hazard ratio (HR) = 1.59, P = 0.011). Safety profile according to genotype status of V297 L failed to find significant difference. Interestingly, the expression of KDR mRNA of patients with CT/TT genotype was significantly higher than that of patients with CC genotype in the 58 cancer tissue specimens (P < 0.001). CONCLUSION: The clinical comes of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimens might be impacted by polymorphism V297 L through mediating the mRNA expression of KDR.

Influence of VEGFR2 gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage SCLC: a real-world retrospective study.

PURPOSE: Great individual differences were observed regarding the efficacy of apatinib clinically. The aim of present study was to investigate the influence of vascular endothelial growth factor receptor2 (VEGFR2) gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 128 patients with chemotherapy-refractory ES-SCLC who were treated with apatinib at an initial dosage of 250 or 500 mg were included in this study. The change of target lesions was assessed. Overall response rate (ORR) was evaluated. Prognosis was carried out and safety profile was documented. Additionally, peripheral blood and biopsy cancer tissue specimens of the patients with SCLC were collected for the analysis of polymorphism and VEGFR2 gene mRNA expression, respectively. The association between genotype status and baseline characteristics was performed. Univariate analysis of genotype status and prognosis was carried out using Kaplan-Meier survival analysis and multivariate analysis were adjusted by Cox regression analysis. RESULTS: Efficacy of apatinib included partial response (PR) in 15 patients, stable disease (SD) in 86 patients, progressive disease (PD) in 27 patients. Therefore, ORR of the 128 patients with ES-SCLC was 11.7%, and disease control rate (DCR) was 78.9%. Prognosis suggested that the median progression-free survival (PFS) and overall survival (OS) of the 128 patients with ES-SCLC was 4.2 months and 8.2 months, respectively. The polymorphism analysis focusing on VEGFR2 gene indicated that one single nucleotide polymorphism 889C>T was of clinical significance. Prevalence of 889C>T among the 128 patients with SCLC were as follows: CC genotype 87 cases (68.0%), CT genotype 38 cases (29.7%) and TT genotype 3 cases (2.3%), the minor allele frequency of 889C>T was 0.17, which was in accordance with Hardy-Weinberg Equilibrium (P = 0.628). Patients with CT and TT genotypes were merged in the subsequent analysis. Prognosis analysis exhibited that the median PFS of patients with CT/TT genotype and CC genotype was 3.3 and 5.0 months, respectively (P = 0.02). Furthermore, the median OS of patients was 5.5 and 9.0 months, respectively (P = 0.008). Additionally, multivariate Cox regression analysis of OS demonstrated that CT/TT genotype was an independent factor for OS [Hazard ratio (HR) = 0.64, P = 0.019]. However, the safety profile according to genotype status of 889C>T failed to show significant difference. Interestingly, mRNA expression analysis suggested that the mRNA expression of VEGFR2 in cancer tissues were significantly different according to CC and CT/TT genotypes (P < 0.001). CONCLUSION: The administration with apatinib for patients with chemotherapy-refractory ES-SCLC was of potential clinical significance. The clinical outcomes of patients with ES-SCLC who were treated with apatinib could be impacted by VEGFR2 889C>T polymorphism through mediating the VEGFR2 mRNA expression.

Lung cancer chemotherapy using nanoparticles: Enhanced target ability of redox-responsive and pH-sensitive cisplatin prodrug and paclitaxel.

Platinum-based combination therapy is more effective and less toxic, but lack of targeting, and is not capable to enrich in the tumor zone. To obstacle these drawbacks, prodrug and nanotechnology strategies have been investigated in this study. GSH-responsive and pH-responsive cisplatin prodrug was synthesized. Cisplatin prodrug and paclitaxel co-loaded nanoparticles: DDP-P/PTX NPs were constructed. The drug release behavior and cytotoxicity of nanoparticles was assessed in vitro. In vivo anticancer efficiency and toxicity were evaluated on lung cancer bearing mice animal model. DDP-P/PTX NPs had a nanoscale size of 112.9 ± 3.5 nm. A reduction and pH triggered drug release with a synergistic tumor cell inhibition ability was observed by DDP-P/PTX NPs. DDP-P/PTX NPs also exhibited high tumor distribution, low systemic toxicity and remarkable antitumor effects in vivo. DDP-P/PTX NPs could be applied as promising anticancer system for the treatment of NSCLC.

Tumor-associated eosinophilia in a patient with EGFR-positive, MET-amplified lung adenocarcinoma refractory to targeted therapy: a case report and review of literature.

Paraneoplastic eosinophilia is a rare complication observed in 1% solid tumor cases and appears to have tumor type-dependent prognostic impact, in which the increased eosinophil count was generally associated with unfavorable prognosis. In the English literature, more than 20 patients have been reported of eosinophilia associated with primary non-small cell lung cancer (NSCLC) at diagnosis, all of whom underwent either surgery, chemotherapy, or symptomatic therapy. Herein, we describe clinical course a stage IV NSCLC patient with paraneoplastic eosinophilia and leukocytosis and receiving targeted therapy. A 64-year-old male former smoker was diagnosed with lung adenocarcinoma harboring EGFR L858R mutation and MET amplification. Blood eosinophilia was manifested at diagnosis and confirmed to be paraneoplastic by eliminating other potential causes. The disease progressed rapidly within a month on EGFR inhibitor icotinib and then within three months on icotinib plus crizotinib after rapid response within the first month. A multi-target kinase inhibitor anlotinib was added, and the disease progressed one month later despite initial self-reported asymptomatic high-performance status. The patient was lost to subsequent follow-ups. Radiographic evaluation of disease control or progression coincided with respective distinct alleviation or worsening of eosinophilia. Consistent with previous reports of poor clinical outcome associated with blood eosinophilia, our results suggested a negative prognostic impact in EGFR-/MET-altered NSCLC. This case is, to the best of our knowledge, the first to provide evidence for blood eosinophilia paralleling disease progression in an EGFR- and MET-altered lung adenocarcinoma under targeted therapy, which suggested negative prognostic impact of blood eosinophilia in driver-positive NSCLC.

miR-19a/b modulates lung cancer cells metastasis through suppression of MXD1 expression.

Increasing evidence has shown that microRNA (miRNA) is extensively involved in the pathophysiology of lung cancer. Microarray data demonstrated the increasing levels of miR-19a in the peripheral blood from patients suffering from lung cancer, which is closely associated with poor prognosis of lung cancer. However, the underlying molecular mechanism of miR-19a remains to be determined. The results of the present study showed a higher expression of miR-19a compared with normal bronchial epithelial cells. Furthermore, lentivirus vectors were constructed to establish cell lines that overexpressed and knocked out miR-19a in order to study the role of miR-19a on the metastasis and proliferation of lung cancer cells. Investigation into the underlying mechanism of miR-19a, revealed that MXD1 may be the key gene targeting miR-19a, participating in the process of proliferation and metastasis of lung cancer cells.

Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin.

BACKGROUND/AIMS: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC. METHODS: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model. RESULTS: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin-silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors. CONCLUSION: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.