Massive Vespa basalis stings induce an envenoming syndrome.

Envenoming syndrome induced by massive Vespa basalis stings is a critical condition. Severe systemic reaction may present with hemolytic activity and rhabdomyolysis, leading diffuse alveolar hemorrhage, adult respiratory distress syndrome, coagulopathy, and multiple organs failure. In severe envenoming syndrome population, extracorporeal membrane oxygenation (ECMO) may be considered for unstable hemodynamic status. However, few studies reported ECMO in venom-induced disseminated intravascular coagulation patients. Here, we provide a case presented with pulmonary hemorrhage due to multiple Vespa basalis stings tried to rescue by veno-arterial extracorporeal membrane oxygenation. We also highlight that early recognition of venom-induced disseminated intravascular coagulation by checking coagulation profile in high risk patients may prevent from poor outcome.

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) leads to increased patients' mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863-0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP.

Vagal nerve endings in visceral pleura and triangular ligaments of the rat lung.

The inner thoracic cavity is lined by the parietal pleura, and the lung lobes are covered by the visceral pleura. The parietal and visceral plurae form the pleural cavity that has negative pressure within to enable normal respiration. The lung tissues are bilaterally innervated by vagal and spinal nerves, including sensory and motor components. This complicated innervation pattern has made it difficult to discern the vagal vs. spinal processes in the pulmonary visceral pleura. With and without vagotomy, we identified vagal nerve fibres and endings distributed extensively in the visceral pleura ('P'-type nerve endings) and triangular ligaments ('L'-type nerve endings) by injecting wheat germ agglutinin-horseradish peroxidase as a tracer into the nucleus of solitary tract or nodose ganglion of male Sprague-Dawley rats. We found the hilar and non-hilar vagal pulmonary pleural innervation pathways. In the hilar pathway, vagal sub-branches enter the hilum and follow the pleural sheet to give off the terminal arborizations. In the non-hilar pathway, vagal sub-branches run caudally along the oesophagus and either directly enter the ventral-middle-mediastinal left lobe or follow the triangular ligaments to enter the left and inferior lobe. Both vagi innervate: (i) the superior, middle and accessory lobes on the ventral surfaces that face the heart; (ii) the dorsal-rostral superior lobe; (iii) the dorsal-caudal left lobe; and (iv) the left triangular ligament. Innervated only by the left vagus is: (i) the ventral-rostral and dorsal-rostral left lobe via the hilar pathway; (ii) the ventral-middle-mediastinal left lobe and the dorsal accessory lobe that face the left lobe via the non-hilar pathway; and (iii) the ventral-rostral inferior lobe that faces the heart. Innervated only by the right vagus, via the non-hilar pathway, is: (i) the inferior (ventral and dorsal) and left (ventral only) lobe in the area near the triangular ligament; (ii) the dorsal-middle-mediastinal left lobe; and (iii) the right triangular ligament. Other regions innervated with unknown vagal pathways include: (i) the middle lobe that faces the superior and inferior lobe; (ii) the rostral-mediastinal inferior lobe that faces the middle lobe; and (iii) the ventral accessory lobe that faces the diaphragm. Our study demonstrated that most areas that face the dorsal thoracic cavity have no vagal innervation, whereas the interlobar and heart-facing areas are bilaterally or unilaterally innervated with a left-rostral vs. right-caudal lateralized innervation pattern. This innervation pattern may account for the fact that the respiratory regulation in rats has a lateralized right-side dominant pattern.

Targeting insulin-like growth factor-binding protein-3 by microRNA-125b promotes tumor invasion and poor outcomes in non-small-cell lung cancer.

Insulin-like growth factor-binding protein-3 acts as a tumor suppressor that inhibits the PI3K/AKT signaling pathway due to blocking insulin growth factor-1 binding to its receptor. We hypothesized that insulin-like growth factor-binding protein-3 might be targeted by microRNA-125b and promote tumor invasion and poor outcome in non-small-cell lung cancer via activation of the PI3K/AKT signaling pathway. Real-time polymerase chain reaction and immunohistochemistry were performed to determine the level of microRNA-125b, insulin-like growth factor-binding protein-3 messenger RNA, and phosphorylated-AKT expression in 105 tumors from non-small-cell lung cancer patients. Low insulin-like growth factor-binding protein-3 messenger RNA levels and positive phosphorylated-AKT expression were more commonly found in patients with high microRNA-125b tumors than low microRNA-125b tumors. A poorer overall survival and relapse-free survival were observed in patients with high microRNA-125b tumors than low-microRNA-125b tumors in p53-mutated patients, but not in p53-wild-type patients. Mechanistically, microRNA-125b promotes invasion ability in p53-mutated cells via the PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, but this effect was not observed in p53-wild-type cells. An increase in phosphorylated-AKT expression due to targeting of insulin-like growth factor-binding protein-3 by microRNA-125b was responsible for cell invasion in p53-mutated cells. In conclusion, the microRNA-125b level promotes invasive ability in p53-mutated cells via PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, thereby resulting in p53-mutated non-small-cell lung cancer patients with poor outcomes.

Elevated Plasma Matrix Metalloproteinase-9 and Its Correlations with Severity of Disease in Patients with Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) increases patient mortality and medical expenditure, and a real-time and reliable method for the rapid diagnosis of VAP may help reduce fatal complications. Matrix metalloproteinases-9 (MMP-9) is considered significant in the pathogenesis of lung inflammation and infection. Therefore, we examined its relationship with the clinical course of VAP. This retrospective observational study recruited 30 healthy volunteers, 12 patients who used mechanical ventilation without the development of VAP (hereafter, patients without VAP), and 30 patients with a clinical diagnosis of VAP (hereafter, patients with VAP). The activity and level of plasma MMP-9 were determined through a gelatin zymography assay and ELISA. Our results report that both plasma MMP-9 activity and concentration were significantly elevated in the acute stage of patients with VAP when compared with control group and patients without VAP (p < 0.001). Subsequently, the plasma MMP-9 of patients with VAP decreased significantly after antibiotic treatment. Furthermore, plasma MMP-9 concentration was positively correlated with the clinical pulmonary infection score (r = 0.409, p = 0.007), WBCs (r = 0.620, p < 0.001), and neutrophils counts (r = 0.335, p = 0.035). In addition, plasma MMP-9 is an excellent tool for recognizing VAP when the cutoff level is set to 92.62 ng/mL (AUC = 0.863, 95% CI = 0.761 to 0.932). In conclusions, we concluded that MMP-9 levels play a role in the development of VAP and might have the potential to be applied in the development of VAP therapies.

Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKß expression.

Magnesium superoxide dismutase (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, whereas, in turn, SOD2 expression is regulated by p53 to modulate lung tumorigenesis. In this study, we found that the level of SOD2 expression in a panel of lung cancer cells was negatively correlated with that of NK2 homeobox 1 (NKX2-1) but was not associated with p53 status. Mechanistic studies indicated that a decrease in NKX2-1 caused by SOD2-activated IKKß transcription was achieved by derepression of binding of Sp1 to the IKKß promoter. Immunoprecipitation, glutathione S-transferase pull-down experiments and electrophoretic mobility shift assays demonstrated a direct interaction between NKX2-1 and Sp1, blocking Sp1-mediated IKKß transcription. SOD2-mediated nuclear factor-kappaB activation, via elevation of IKKß transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, because of development of the epithelial-to-mesenchymal transition. The expression level of NKX2-1 messenger RNA was negatively associated with the extent of SOD immunostaining and the IKKß messenger RNA expression level in lung tumors. The extent of SOD2 immunostaining and IKKß messenger RNA levels may independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. In summary, we found that SOD2 activates nuclear factor-kappaB signaling by increasing IKKß transcription, which results in progression of lung adenocarcinoma and poorer patient outcomes. We suggest that IKKß may potentially be targeted to improve outcomes in patients with SOD2-positive tumors.

Distinct evolution of ST11 KL64 Klebsiella pneumoniae in Taiwan.

Carbapenem-resistant ST11_KL64 Klebsiella pneumoniae emerged as a significant public health concern in Taiwan, peaking between 2013 and 2015, with the majority of isolates exhibiting OXA-48 as the sole carbapenemase. In this study, we employed whole-genome sequencing to investigate the molecular underpinnings of ST11_KL64 isolates collected from 2013 to 2021. Phylogenomic analysis revealed a notable genetic divergence between the ST11_KL64 strains in Taiwan and those in China, suggesting an independent evolutionary trajectory. Our findings indicated that the ST11_KL64_Taiwan lineage originated from the ST11_KL64 lineage in Brazil, with recombination events leading to the integration of ICEKp11 and a 27-kb fragment at the tRNAASN sites, shaping its unique genomic landscape. To further elucidate this unique sublineage, we examined the plasmid contents. In contrast to ST11_KL64_Brazil strains, which predominantly carried blaKPC-2, ST11_KL64_Taiwan strains exhibited the acquisition of an epidemic blaOXA-48-carrying IncL plasmid. Additionally, ST11_KL64_Taiwan strains consistently harbored a multi-drug resistance IncC plasmid, along with a collection of gene clusters that conferred resistance to heavy metals and the phage shock protein system via various Inc-type plasmids. Although few, there were still rare ST11_KL64_Taiwan strains that have evolved into hypervirulent CRKP through the horizontal acquisition of pLVPK variants. Comprehensive characterization of the high-risk ST11_KL64 lineage in Taiwan not only sheds light on its epidemic success but also provides essential data for ongoing surveillance efforts aimed at tracking the spread and evolution of ST11_KL64 across different geographical regions. Understanding the molecular underpinnings of CRKP evolution is crucial for developing effective strategies to combat its emergence and dissemination.

PD-L1 expressed from tumor cells promotes tumor growth and invasion in lung cancer via modulating TGF-ß1/SMAD4 expression.

BACKGROUND: Programmed death ligand-1 (PD-L1) has a known association with the prognosis of human cancers because of its ability to alter tumor immune surveillance via its interaction with PD-1. We questioned whether expression of PD-L1 in tumor cells could directly promote tumor growth and invasiveness in non-small cell lung cancer (NSCLC). METHODS: Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate PD-L1 messenger RNA (mRNA) expression in lung tumors. The prognostic value of PD-L1 mRNA was assessed by Cox regression model. Transcriptional regulation of PD-L1 by human papillomavirus (HPV) 16/18 E6 oncoprotein or by epidermal growth factor receptor (EGFR) mutation in lung cancer cells was examined by Western blot and luciferase reporter assay. The cell growth and invasion were evaluated by colony formation, soft agar growth, and Boyden chamber assay. RESULTS: The PD-L1 mRNA levels showed a positive association with HPV 16/18 E6 oncoprotein and with EGFR mutation in 223 surgically resected NSCLC patients. The prognostic significance of PD-L1 was more commonly observed in patients with high PD-L1/E6 positive and high PD-L1/EGFR mutant tumors. Mechanistically, upregulation of PD-L1 transcription by E6 or mutant EGFR occurred largely through the ERK-C/EBPß-TLR4-NF-κB cascade. PD-L1 promotes the efficacy of colony formation, soft agar growth, and cell invasion. PD-L1 upregulates BAG-1 to reduce transforming growth factor (TGF)-ß1 expression, and the decrease in SMAD4 because of TGF-ß1 occurs through the p53/microRNA (miR)-224 axis. The decreases in TGF-ß1 and SMAD4 are responsible for PD-L1-mediated cell invasiveness. CONCLUSION: Induction of PD-L1 by E6 oncoprotein or mutant EGFR through the ERK-C/EBPß-TLR4-NF-κB cascade may promote tumor growth and invasiveness in NSCLC because of decreasing TGF-ß1 and SMAD4 expression.

Risk factors and prognoses of invasive Candida infection in surgical critical ill patients with perforated peptic ulcer.

BACKGROUND: The risk of invasive Candida infection (ICI) is high in patients with perforated peptic ulcer (PPU) who received laparotomy or laparoscopic surgery, but the risk factors and predictors of morbidity outcomes remain uncertain. This study aims to identify the risk factors of ICI in surgical critically ill PPU patients and to evaluate the impact on patient's outcomes. METHODS: This is a single-center, retrospective study, with a total of 170 surgical critically ill PPU patients. Thirty-seven patients were ICI present and 133 were ICI absent subjects. The differences in pulmonary complications according to invasive candidiasis were determined by the Mann-Whitney U test. Evaluation of predictors contributing to ICI and 90-day mortality was conducted by using multivariate logistic regression analysis. RESULTS: Candida albicans was the primary pathogen of ICI (74.29%). The infected patients had higher incidence of bacteremia (p < 0.001), longer intensive care unit (p < 0.001) and hospital (p < 0.001) stay, longer ventilator duration (p < 0.001) and increased hospital mortality (p = 0.02). In the multivariate analysis, serum lactate level measured at hospital admission was independently associated with the occurrence of ICI (p = 0.03). Liver cirrhosis (p = 0.03) and Sequential Organ Failure Assessment (SOFA) score (p = 0.007) were independently associated with the 90-day mortality. CONCLUSIONS: Blood lactate level measured at hospital admission could be a predictor of ICI and the surgical critically ill PPU patients with liver cirrhosis and higher SOFA score are associated with poor outcomes.

Microevolution of CG23-I Hypervirulent Klebsiella pneumoniae during Recurrent Infections in a Single Patient.

CG23-I lineage constitutes the majority of hypervirulent Klebsiella pneumoniae. A diabetic patient suffered six episodes of infections caused by CG23-I K. pneumoniae. A total of nine isolates were collected in 2020. We performed whole-genome sequencing to elucidate the within-patient evolution of CG23-I K. pneumoniae. The maximum pairwise difference among the nine longitudinally collected isolates was five single nucleotide polymorphisms. One of the mutations was at the Asp87 position of GyrA. Four indels were identified, including an initiator tRNAfMet duplication, a tRNAArg deletion, a 7-bp insertion, and a 22-bp deletion. All 9 isolates had the genomic features of CG23-I K. pneumoniae, a chromosome-borne ICEKp10, and a large virulence plasmid. The carriage of a complete set of genes for the biosynthesis of colibactin by ICEKp10 gave the nine isolates an ability to cause DNA damage to RAW264.7 cells. Compared with the initial isolate, the last isolate with an additional copy of initiator tRNAfMet grew faster in a nutrient-limiting condition and exhibited enhanced virulence in BALB/c mice. Collectively, we characterized the within-patient microevolution of CG23-I K. pneumoniae through an in-depth comparison of genome sequences. Using the in vitro experiments and mouse models, we also demonstrated that these genomic alterations endowed the isolates with advantages to pass through in vivo selection. IMPORTANCE CG23-I is a significant lineage of hypervirulent Klebsiella pneumoniae. This study characterizes the within-patient microevolution of CG23-I K. pneumoniae. Selective pressures from continuous use of antibiotics favored point mutations contributing to bacterial resistance to antibiotics. The duplication of an initiator tRNAfMet gene helped CG23-I K. pneumoniae proliferate to reach a maximal population size during infections. For longer persistence inside a human host, the large virulence plasmid evolved with more flexible control of replication through duplication of the iteron-1 region. With the genomic alterations, the last isolate had a growth advantage over the initial isolate and exhibited enhanced virulence in BALB/c mice. This study gives us a deeper understanding of the genome evolution during the within-patient pathoadaptation of CG23-I K. pneumoniae.

Down-regulation of granulocyte-macrophage colony-stimulating factor by 3C-like proteinase in transfected A549 human lung carcinoma cells.

BACKGROUND: Severe Acute Respiratory Syndrome (SARS) is a severe respiratory illness caused by a novel virus, the SARS coronavirus (SARS-CoV). 3C-like protease (3CLpro) of SARS-CoV plays a role in processing viral polypeptide precursors and is responsible of viral maturation. However, the function of 3CLpro in host cells remains unknown. This study investigated how the 3CLpro affected the secretion of cytokines in the gene-transfected cells. RESULTS: From immunofluorescence microscopy, the localization of c-myc tagged 3CLpro was detected both in the cytoplasm and nucleus of transfected A549 cells. Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) was significantly decreased in 3CLpro-transfected cells by both RT-PCR and ELISA, but without changes in other cytokines, i.e., IL-1ß, IL-6, IL-8, IL12p40, TNF-α, and TGF-ß. Furthermore, the protein levels of NF-kB decreased in 3CLpro-transfected A549 cells when compared to EGFP transfected cells. CONCLUSIONS: Our results suggest that the 3CLpro may suppress expression of GM-CSF in transfected A549 cells through down-regulation of NF-kB production.

Improved trends of lung cancer mortality-to-incidence ratios in countries with high healthcare expenditure.

BACKGROUND: Lung cancer stage has a significant impact on prognosis, and early detection of lung cancer relies on screenings. Despite the strong relationship between screening and lung cancer staging, the role of healthcare expenditure in lung cancer outcomes remains unknown. The aim of this study was to evaluate the relationship between economic status and clinical outcomes in lung cancer. METHODS: Data were obtained from GLOBOCAN and the World Health Organization. Mortality-to-incidence ratios (MIRs) and their change over time, calculated as the difference between the MIRs of 2012 and 2018 (δMIR), were used to evaluate their correlation to expenditures on healthcare and human development index (HDI) disparities via Spearman's rank correlation coefficient. RESULTS: Regions such as North America have relatively high crude incidence rates but low MIR values. Furthermore, countries with lower crude incidence rates spent less on healthcare. The results show significant negative associations between HDI, current health expenditure (CHE) per capita, CHE as a percentage of gross domestic product (CHE/GDP), and MIR. As for MIR and δMIR, countries with favorable MIRs also showed improving MIRs based on δMIR. CONCLUSIONS: HDI, CHE per capita, CHE/GDP, and development status play noticeable roles in the prognosis of lung cancer, leading to large disparities in clinical outcomes.

Respiratory care for the critical patients with 2019 novel coronavirus.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted through respiratory droplets, aerosols and close contact. Cross infections occur because viruses spread rapidly among humans. Nineteen percent (19%) of the infected patients developed severe pneumonia and acute respiratory distress syndrome (ARDS). Hypoxemia usually occurs and patients may require oxygen therapy or mechanical ventilation (MV) support. In this article, recently published clinical experience and observational studies were reviewed. Corresponding respiratory therapy regarding different stages of infection is proposed. Infection control principles and respiratory strategies including oxygen therapy, non-invasive respiratory support (NIRS), intubation evaluation, equipment preparation, ventilator settings, special maneuvers comprise of the prone position (PP), recruitment maneuver (RM), extracorporeal membrane oxygenation (ECMO), weaning and extubation are summarized. Respiratory equipment and device disinfection recommendations are worked up. We expect this review article could be used as a reference by healthcare workers in patient care while minimizing the risk of environmental contamination.

The Relationship between Long Noncoding RNA H19 Polymorphism and the Epidermal Growth Factor Receptor Phenotypes on the Clinicopathological Characteristics of Lung Adenocarcinoma.

The aim of the current study is to investigate potential associations among Long Noncoding RNA (LncRNA) H19 single nucleotide polymorphism (SNP) and epidermal growth factor receptor (EGFR) phenotypes on the clinicopathological characteristics of lung adenocarcinoma (LADC). Five loci of LncRNA H19 SNPs (rs217727, rs2107425, rs2839698, rs3024270, and rs3741219) were genotyped by using TaqMan allelic discrimination in 223 LADC patients with wild-type EGFR phenotype and 323 LADC individuals with EGFR mutations. After the statistical analyses, patients with the EGFR mutation were related to a higher distribution frequency of rs217727 SNP CT heterozygote (p = 0.030), and the female population with EGFR mutation demonstrated a higher distribution frequency of rs217727 SNP CT heterozygote (p < 0.001) and rs2107425 CT heterozygote (p = 0.002). In addition, the presence of LncRNA H19 SNP rs217727 T allele (CT + TT) in patients with EGFR wild-type was associated to higher tumor T status (stage III or IV, p = 0.037) and poorer cell differentiation status (poor differentiation, p = 0.012) compared to those EGFR wild-type individuals with LncRNA H19 SNP rs217727 CC allele. Besides, a prominently higher tumor T status was found in subjects with LncRNA H19 SNP rs2107425 T allele (CT + TT) (stage III or IV, p = 0.007) compared to EGFR wild-type LADC individuals with LncRNA CC allele in EGFR wild-type patients. Our findings suggest that the presence of LncRNA H19 SNP rs217727 is related to the EGFR mutation in LADC patients, and the LncRNA H19 SNP rs217727 and rs2107425 are associated with progressed tumor status for LADC patients with EGFR wild-type.

Potential Impacts of Interleukin-17A Promoter Polymorphisms on the EGFR Mutation Status and Progression of Non-Small Cell Lung Cancer in Taiwan.

Non-small cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common histopathological subtype. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR tyrosine kinase inhibitors. Interleukin (IL)-17A secreted by T-helper 17 lymphocytes is a proinflammatory cytokine that plays an important role in cancer pathogenesis. The present study was designed to investigate the possible associations among IL-17A genetic polymorphisms, EGFR mutation status, and the clinicopathologic development of LUAD in a Taiwanese population. Our study population consisted of 277 LUAD patients harboring the wild-type (WT) EGFR or a mutant (MT) EGFR. Four single-nucleotide polymorphisms (SNPs) of IL-17A in the peripheral blood, including rs8193036(C > T), rs8193037(G > A), rs2275913(G > A), and rs3748067(C > T) loci, were genotyped using a TaqMan allelic discrimination assay. Our results showed that none of these IL-17A SNPs were correlated with the risk of developing mutant EGFR. However, patients with a smoking habit who carried the GA genotype of IL-17A rs8193037 had a significantly lower susceptibility to EGFR mutations (adjusted odds ratio (AOR): 0.225; 95% confidence interval (CI): 0.056~0.900, p = 0.035). Moreover, compared to individuals carrying the CC genotype of rs8193036 at IL-17A, T-allele carriers (CT + TT) were at higher risk of developing more-advanced stages (stage III or IV; p = 0.020). In the WT EGFR subgroup analysis, IL-17A rs8193036 T-allele carriers had higher risks of developing an advanced tumor stage (p = 0.016) and lymphatic invasion (p = 0.049). Further analyses of clinical datasets revealed correlations of IL-17 receptor A (IL-17RA) and IL-17RC expressions with a poor prognosis of LUAD patients with a smoking history or with higher levels of tumor-infiltrating lymphocytes. In conclusion, our results suggested that two functional promoter polymorphisms of IL-17A, i.e., rs8193036 and rs8193037, were associated with the EGFR mutation status and progression in LUAD patients, indicating that these two genetic variants might act as possible markers for predicting patients' clinical prognoses.

Author Correction: PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via ß-catenin-mediated stemness.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Association of nuclear localization of SHP2 and YAP1 with unfavorable prognosis in non-small cell lung cancer.

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed in cytoplasmic localization, which in turn confers tumor malignancy and poor prognosis in various human cancers. YAP1 interacts with SHP2 to promote translocation of SHP2 to nucleus, which consequently promotes Wnt target activation. However, the oncogenic role of the nuclear localization of SHP2 in human cancers remains unclear. We hypothesized that nuclear SHP2 localization, in combination with nuclear YAP1 expression, could be associated with poor overall survival (OS) and relapse free survival (RFS) due to an increase in cyclin D1 and c-Myc mRNA expression following activation of Wnt/ß-catenin signaling. Immunohistochemical analysis of SHP2 and YAP1 protein expression in 102 tumors resected from patients with NSCLC revealed that nuclear SHP2 expression was well correlated with nuclear YAP1 expression (P < 0.001). Evaluation of cyclin D1 and c-Myc mRNA levels by the real-time reverse-phase polymerase chain reaction (RT-PCR) revealed that patients with high cyclin D1 and high c-Myc mRNA expressing tumors more commonly showed high nuclear YAP1 and high nuclear SHP2 (high/high) rather than the high/low, low/high, or low/low combinations (P < 0.001 for cyclin D1 and c-Myc). Kaplan-Meier and Cox-regression models showed OS and RFS to be poorer in patients in the high/high subgroup than in the low/low subgroup (OS: HR = 2.85, 95% CI, 1.52-5.35, P = 0.001; RFS: HR = 2.55, 95% CI, 1.37-4.72, P = 0.003). No prognostic significance was observed for the other two subgroups (low/high and high/low) when compared to the low/low subgroup in this study population. Therefore, we suggest that the prognostic value of SHP2 could reflect the nuclear localization of SHP2 and its interaction with nuclear YAP1, which led to subsequent upregulation of cyclin D1 and c-Myc mRNA expression via activation of the Wnt/ß-catenin signaling pathway.

A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop.

Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop. A retrospective study was conducted to examine whether the expression of miR-630 and YAP1 could be associated with TKI therapeutic response in patients with lung adenocarcinoma. Results: Low miR-630 expression may confer TKI resistance via increased SP1 binding to the miR-630 promoter due to ERK activation by YAP1 de-targeting. Persistent activation of ERK signaling via the miR-630/YAP1/ERK feedback loop may be responsible for TKI resistance in EGFR-mutated cells. Moreover, a decrease in Bad expression by its phosphorylation at Serine 75 through ERK activation conferred low miR-630-mediated TKI resistance by modulating the apoptotic pathway. Xenographic tumors induced by miR-630-knockdown PC9 and PC9GR cells in nude mice were nearly suppressed by the combination of gefitinib with the YAP1 inhibitor verteporfin or an MEK/ERK inhibitor AZD6244. Patients with low miR-630 and high YAP1 expressing tumors had a higher prevalence of unfavorable responses to TKI therapy and poorer outcomes when compared with their counterparts. Conclusion: MiR-630 may be a potential biomarker for the prediction of TKI therapeutic response and outcome in patients with lung adenocarcinoma.