Adaptive autophagy reprogramming in Schwann cells during peripheral demyelination.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7-dependent formation of a "secretory phagophore (SP)" and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

TWIST mediates resistance to paclitaxel by regulating Akt and Bcl-2 expression in gastric cancer cells.

The transcription factor TWIST has been reported to play an important role in tumor progression as well as resistance to anti-cancer drugs. However, the role of TWIST in gastric cancer and the molecular mechanisms by which this protein elicits drug resistance remain poorly understood. We transfected gastric cancer cell lines with lentiviral vector to generate TWIST-overexpressing stable cell lines. Our study showed that overexpression of TWIST not only increased cell migration and invasion but also induced resistance to the anti-cancer drug paclitaxel in gastric cancer. Paclitaxel increased gastric cancer cell death in dose-dependent manner; this was decreased following TWIST overexpression. Furthermore, treatment with paclitaxel decreased Akt phosphorylation and Bcl-2 expression, whereas these effects were suppressed by TWIST overexpression. Treatment of cells with Akt inhibitor or small interfering RNA targeting for Bcl-2 led to increased paclitaxel-induced cell death, indicating that TWIST elicits resistance to paclitaxel via the regulation of the Akt and Bcl-2 pathway. Our results suggest an underlying mechanism for TWIST-mediated paclitaxel resistance and indicate that TWIST represents a potential target for overcoming paclitaxel resistance in gastric cancer cells.

Transcriptome analysis of paired primary colorectal carcinoma and liver metastases reveals fusion transcripts and similar gene expression profiles in primary carcinoma and liver metastases.

BACKGROUND: Despite the clinical significance of liver metastases, the difference between molecular and cellular changes in primary colorectal cancers (CRC) and matched liver metastases is poorly understood. METHODS: In order to compare gene expression patterns and identify fusion genes in these two types of tumors, we performed high-throughput transcriptome sequencing of five sets of quadruple-matched tissues (primary CRC, liver metastases, normal colon, and liver). RESULTS: The gene expression patterns in normal colon and liver were successfully distinguished from those in CRCs; however, RNA sequencing revealed that the gene expression between primary CRCs and their matched liver metastases is highly similar. We identified 1895 genes that were differentially expressed in the primary carcinoma and liver metastases, than that in the normal colon tissues. A major proportion of the transcripts, identified by gene expression profiling as significantly enriched in the primary carcinoma and metastases, belonged to gene ontology categories involved in the cell cycle, mitosis, and cell division. Furthermore, we identified gene fusion events in primary carcinoma and metastases, and the fusion transcripts were experimentally confirmed. Among these, a chimeric transcript resulting from the fusion of RNF43 and SUPT4H1 was found to occur frequently in primary colorectal carcinoma. In addition, knockdown of the expression of this RNF43-SUPT4H1 chimeric transcript was found to have a growth-inhibitory effect in colorectal cancer cells. CONCLUSIONS: The present study reports a high concordance of gene expression in the primary carcinoma and liver metastases, and reveals potential new targets, such as fusion genes, against primary and metastatic colorectal carcinoma.

Novel peptides functionally targeting in vivo human lung cancer discovered by in vivo peptide displayed phage screening.

Discovery of the cancer-specific peptidic ligands have been emphasized for active targeting drug delivery system and non-invasive imaging. For the discovery of useful and applicable peptidic ligands, in vivo peptide-displayed phage screening has been performed in this study using a xenograft mouse model as a mimic microenvironment to tumor. To seek human lung cancer-specific peptides, M13 phage library displaying 2.9 × 10(9) random peptides was intravenously injected into mouse model bearing A549-derived xenograft tumor through the tail vein. Then the phages emerged from a course of four rounds of biopanning in the xenograft tumor tissue. Novel peptides were categorized into four groups according to a sequence-homology phylogenicity, and in vivo tumor-targeting capacity of these peptides was validated by whole body imaging with Cy5.5-labeled phages in various cancer types. The result revealed that novel peptides accumulated only in adenocarcinoma lung cancer cell-derived xenograft tissue. For further confirmation of the specific targeting ability, in vitro cell-binding assay and immunohistochemistry in vivo tumor tissue were performed with a selected peptide. The peptide was found to bind intensely to lung cancer cells both in vitro and in vivo, which was efficiently compromised with unlabeled phages in an in vitro competition assay. In conclusion, the peptides specifically targeting human lung cancer were discovered in this study, which is warranted to provide substantive feasibilities for drug delivery and imaging in terms of a novel targeted therapeutics and diagnostics.

Age and sex differences in comorbidities in adult temporomandibular disorders: A cross-sectional study using Korea National Health and Nutrition Examination Survey (KNHANES).

OBJECTIVES: To investigate the relationship between Temporomandibular disorder (TMD) and associated comorbidities in groups matched according to age and sex. METHODS: Using data from the cross-sectional fifth Korea National Health and Nutrition Examination Survey (KNHANES). Of the 25,534 eligible KNHANES, 17,762 adults aged ≥19 years who responded to survey questionnaire on TMD and comorbidities. Subjects were classified into eight groups according to age and sex. Logistic regression analyses were performed to evaluate the association between TMD and comorbidities according to age and sex. RESULTS: Of the enrolled participants, 2,107 (11.86%) complained of ≥1 TMD symptoms. In all groups, odds ratios (ORs) for prevalence of TMD were >1 in those with tinnitus. Rhinitis was closely associated with TMD in 6 groups. ORs for TMD with comorbidities according to age and sex were as follows: hypertension, men aged 50-64 years (OR 0.62; CI 0.41-0.94); ischemic heart disease, men aged 35-49 years (4.38; 1.54-12.47); osteoarthritis, women aged 50-64 years (1.38; 1.03-1.86); diabetes mellitus, men aged 35-49 years (0.21; 0.05-0.88); depression, men aged 50-64 years (1.68; 1.00-2.83), women aged 35-49 years (1.39; 1.05-1.85) and women aged 65-80 years (2.01; 1.46-2.77); migraine, men aged 50-64 years (1.60; 1.14-2.25), women aged d35-49 years (1.44; 1.14-1.81) and women aged 35-49 years (1.43; 1.07-1.90); cold hypersensitivity in the hands and feet, men aged 19-34 years (1.64; 1.05-2.58), men aged 35-49 years (1.68; 1.04-2.70), men aged 65-80 years (1.74; 1.09-2.75) and women aged 35-49 years (1.45; 1.15-1.84); olfaction disorder, men aged 50-64 years (2.49; 1.39-4.43); voice disorder, men aged 50-64 years (2.25; 1.28-3.96) and women aged 65-80 years (1.69; 1.09-2.63). CONCLUSIONS: This study confirmed that the types and effects of comorbidities related to prevalence of TMD may differ according to the patient's age and sex and this result will increase the predictability of the onset of TMD.

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.

ABBREVIATIONS: AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; SYN1: synapsin I.

Correction: Evaluation of class participation in non-face-to-face CPR training for medical students.

[This corrects the article DOI: 10.1371/journal.pone.0278273.].

Analyzing willingness for extracorporeal cardiopulmonary resuscitation in refractory ventricular fibrillation.

Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory ventricular fibrillation/ventricular tachycardia in out-of-hospital cardiac arrest has recently been recommended for selected patients with favorable prognostic features. We aimed to identify factors affecting the willingness of emergency physicians to implement extracorporeal cardiopulmonary resuscitation (ECPR). We conducted a factorial survey with nine experimental vignettes by combining three different scene time intervals and transportation time intervals. Emergency physicians reported willingness to implement ECPR (1-100 points). Respondent characteristics that could affect the willingness were studied. Multilevel analysis of vignettes and respondent factors was conducted using a mixed-effects regression model. We obtained 486 vignette responses from 54 emergency physicians. In the case of longer scene time intervals, there was a significant difference in the willingness scores at 9 and 12 min transportation time intervals. When the pre-hospital time interval was > 40 min, emergency physicians demonstrated lower willingness to implement ECPR. Clinical experience of 15-19 years showed a significant favorable effect on willingness to implement extracorporeal membrane oxygenation (ECMO). However, the mean willingness scores of EPs for ECMO implementation were more than 75 across all vignettes. In ECPR, the prehospital time interval is an important factor, and the willingness of emergency physicians to implement ECMO could be mutually affected by scene time intervals, transportation time intervals, and total prehospital time.

Nurse evaluation of stress levels during CPR training with heart rate variability using smartwatches according to their personality: A prospective, observational study.

BACKGROUND: Cardiopulmonary resuscitation (CPR) is a very critical phenomenon, and to prepare for it, most nurses undertake simulation training, during which learners' stress levels should be managed. This study aims to evaluate nurses' stress levels during CPR simulation training using heart rate variability (HRV) measured with a smartwatch and to determine the correlation between individual personality traits and stress levels. METHODS: This prospective observational study was conducted from July 2020 to December 2021. For nurses participating in advanced life support training with more than six months of clinical experience, their stress levels while performing as a CPR team leader were measured. Regarding stress levels, heart rate data measured with a smartwatch were processed using Kubios HRV Standard software to generate HRV parameters. The personality of participants was evaluated using the Big Five personality test. The degree of stress according to personality was determined using HRV parameters. Consequently, the correlation between personality and stress according to the clinical experience of cardiac arrest was analyzed. RESULTS: Of the 132 participants, 91.7% were female, and the median age of the sample was 27 years. Agreeable personality had the highest score (32.84±3.83). LF power (r = 0.18, p = 0.04) and HF power (r = 0.20, p = 0.02) showed a significant positive correlation with the agreeableness trait. In subgroup analysis according to the cardiac arrest experience, the agreeableness trait had a positive correlation with a standard deviation of NN intervals (r = 0.24, p = 0.01), root-mean-square of successive differences (r = 0.23, p = 0.02), LF Power (r = 0.26, p = 0.01), and HF power (r = 0.23, p = 0.02), but a negative correlation with mean HR (r = -0.22, p = 0.03). CONCLUSION: The clinical experience in cardiac arrest and agreeableness were related to acute stress during training. In the future, it is necessary to apply a scenario of a level suitable for individual personality and experience, and evaluate the level and achievement of students.

Emergency Transport Refusal during the Early Stages of the COVID-19 Pandemic in Gyeonggi Province, South Korea.

We analyzed the changes in patients' clinical characteristics and transport refusal pre- and post-COVID-19 and identified the reasons for transport refusal using emergency medical services run sheet data from pre-COVID-19 (April−December 2019) and post-COVID-19 (April−December 2020) in Gyeonggi Province, South Korea. We included patients aged ≥18 years. Univariate and multivariate logistic regression analyses were performed to identify the relationship between patients' personal factors and clinical characteristics and emergency transport refusal. During the control and study periods, 612,681 cases were reported; the transport refusal rates during the control and study periods were 6.7% and 8.2%, respectively. Emergency transport refusal was associated with younger age, the male sex, a normal mental status, a shock index < 1, and trauma in both the pre- and post-COVID-19 periods. Although fever prevented transport refusal during the pre-COVID-19 period (aOR, 0.620; 95% CI, 0.567−0.679), it became a significant risk factor for transport refusal during the post-COVID-19 period (aOR, 1.619; 95% CI, 1.534−1.709). The most common reason for transport refusal by critically ill patients was "because it was not accepted within the jurisdiction and remote transport was required." It is necessary to expand the response capacity of patients with fever in the community to reduce the refusal of transport by critically ill patients.

Extremity Injuries during Sporting Activities According to Life Course: Focusing on Fractures.

Background: The increased participation in sports has led to an increased number of sports-related injuries. We aimed to identify the incidence of sports-related injuries by life course and the risk factors for sports-related extremity fractures. Methods: We analyzed data of patients with sports-related extremity injuries from Emergency Department-based national injury surveillance systems, obtained from Jan 2013 to Dec 2016. A multiple logistic regression analysis was performed to identify risk factors of extremity fracture by life course after adjusting for sex, injury season, injury time, injury place, sports type, and mechanism of injury. Results: Overall, 23385 patients met our inclusion criteria. Soccer injuries were most common in the 5-14-year (32.4%), 15-24-year (43.0%), and 25-44-year groups (32.7%), and hiking injuries were most common in the 45-64-year (23.6%) and ≥65-year age groups (38.0%). The upper extremity injury and fracture rates were higher in the younger-age group; nevertheless, the injury and fracture rates of the lower extremities increased with increasing age. Moreover, the rate of hip and thigh injuries and fractures increased significantly in the ≥65-year age group. Conclusion: The incidence and severity of sports injuries are affected by player factors and the sports activity itself. The age of players is a major determinant that affects their medical and physiologic conditions and the sport of choice. The strategy for preventing sports injuries should be structured based on age.

Evaluation of class participation in non-face-to-face CPR training for medical students.

BACKGROUND: Cardiopulmonary resuscitation (CPR) education requires that learners practice key skills to promote mastery. Our aim in this study was to evaluate differences in post-education performance and class participation during CPR training between face-to- face (FF) and non-face-to-face (NFF) learning formats. METHODS: This was a randomized controlled study of third-year medical students from two university hospital, allocated to either the FF or NFF format for CPR education. The learning scenario addressed single-person CPR, consisting of chest compression only, and excluded breathing. The Kahoot! application was used for NFF. Between-group comparisons for class participation and CPR skills were based on video recordings. RESULTS: Seventy students participated in our study, with 35 randomly allocated to the FF and NFF groups. There were no between-group differences in terms of age, sex, previous basic life support training, and willingness and confidence in performing CPR. Compared to the FF group, the NFF group demonstrated significant differences during CPR, including fewer calling for assistance and using of defibrillator (p = 0.006), as well as fewer checking for breathing (p = 0.007), and fewer counting during chest compression (p = 0.006). Additionally, < 30% of learners in the NFF group completed rhythm analysis after the last defibrillator shock delivery and resumed immediate chest compression (p < 0.001). All students in both groups passed the post-training assessment. CONCLUSION: Class participation in NFF learning was lower than that in FF learning. Although the post-education evaluation in the NFF group was not inferior, efforts on promoting active participation in NFF learning are required.

Application of the Team Emergency Assessment Measure for Prehospital Cardiopulmonary Resuscitation.

INTRODUCTION: Communication and teamwork are critical for ensuring patient safety, particularly during prehospital cardiopulmonary resuscitation (CPR). The Team Emergency Assessment Measure (TEAM) is a tool applicable to such situations. This study aimed to validate the TEAM efficiency as a suitable tool even in prehospital CPR. METHODS: A multi-centric observational study was conducted using the data of all non-traumatic out-of-hospital cardiac arrest patients aged over 18 years who were treated using video communication-based medical direction in 2018. From the extracted data of 1494 eligible patients, 67 sample cases were randomly selected. Two experienced raters were assigned to each case. Each rater reviewed 13 or 14 videos and scored the TEAM items for each field cardiopulmonary resuscitation performance. The internal consistency, concurrent validity, and inter-rater reliability were measured. RESULTS: The TEAM showed high reliability with a Cronbach's alpha value of 0.939, with a mean interitem correlation of 0.584. The mean item-total correlation was 0.789, indicating significant associations. The mean correlation coefficient between each item and the global score range was 0.682, indicating good concurrent validity. The mean intra-class correlation coefficient was 0.804, indicating excellent agreement. DISCUSSION: The TEAM can be a valid and reliable tool to evaluate the non-technical skills of a team of paramedics performing CPR.

Instructor-led distance learning for training students in cardiopulmonary resuscitation: A randomized controlled study.

STUDY HYPOTHESIS: Cardiopulmonary resuscitation (CPR) training can increase the likelihood of patient survival and better neurological outcomes. However, conventional learning (CL) has cost, time, and space constraints. This study aimed to evaluate whether laypersons who completed instructor-led distance learning (DL) acquired a level of CPR skill comparable to that achieved via CL training. METHODS: This randomized controlled study recruited students from 28 Korean high schools who were randomized to complete instructor-led DL or CL training. The CL training involved classroom-based face-to-face training, whereas the instructor-led DL training was provided online using a videoconferencing system. RESULTS: The study enrolled 62 students who were randomized to the CL group (31 participants) or the DL group (31 participants). Relative to the CL group, the DL group achieved remarkably similar results in terms of most CPR variables. In addition, the DL group had a significant improvement in the mean compression depth (before: 46 mm [interquartile range: 37-52 mm] vs. after: 49 mm [interquartile range: 46-54 mm], p<0.001). CONCLUSIONS: Instructor-led DL can be a suitable alternative to CL for providing CPR training to laypersons. In settings like the current COVID-19 pandemic, where face-to-face CL is not practical, DL may be a useful tool for delivering CPR training.

Factors Associated with High-Quality Cardiopulmonary Resuscitation Performed by Bystander.

Bystander cardiopulmonary dresuscitation (CPR) improves the survival and neurological outcomes of sudden cardiac arrest patients. The rate of bystander CPR is increasing; however, its performance quality has not been evaluated in detail. In this study, emergency medical technicians (EMTs) in the field evaluated bystander CPR quality, and we aimed to investigate the association between bystander information and CPR quality. This retrospective cohort study was based on data included in the Smart Advanced Life Support (SALS) registry between January 2016 and December 2017. We included patients older than 18 years who experienced an out-of-hospital cardiac arrest (OHCA) due to medical causes. Bystander CPR quality was judged to be "high" when the hand positions were appropriate and when compression rates of at least 100/min and compression depths of at least 5 cm were achieved. Among 6,769 eligible patients, 3,799 (58.7%) received bystander CPR, and 6% of bystanders performed high-quality CPR. After adjustment, the occurrence of cardiac arrest at home (adjusted odds ratio (aOR), 95% confidence interval (CI); 0.42, 0.27-0.64), witnessed cardiac arrest (1.45, 1.03-2.06), and younger bystander age all showed associations with one another. High-quality CPR led to a 4.29-fold increase in the chance of neurological recovery. In particular, high-quality CPR in patients aged 60 years showed a significant association compared with other age groups (7.61, 1.41-41.04). The main factor affecting CPR quality in this study was the age of the bystander, and older bystanders found it more difficult to maintain CPR quality. To improve the quality of bystander CPR, training among older bystanders should be the focus.

Hydrogen Peroxide Enhances the Antibacterial Effect of Methylene Blue-based Photodynamic Therapy on Biofilm-forming Bacteria.

Recently, increased attention has been focused on endoscopic disinfection after outbreaks of drug-resistant infections associated with gastrointestinal endoscopy. The aims of this study were to investigate the bactericidal efficacy of methylene blue (MB)-based photodynamic therapy (PDT) on Pseudomonas aeruginosa (P. aeruginosa), which is the major cause of drug-resistant postendoscopy outbreak, and to assess the synergistic effects of hydrogen peroxide addition to MB-based PDT on biofilms. In planktonic state of P. aeruginosa, the maximum decrease was 3 log10 and 5.5 log10 at 20 and 30 J cm-2 , respectively, following MB-based PDT. However, the maximum reduction of colony forming unit (CFU) was decreased by 2.5 log10 and 3 log10 irradiation on biofilms. The biofilm formation was significantly inhibited upon irradiation with MB-based PDT. When the biofilm state of P. aeruginosa was treated with MB-based PDT with hydrogen peroxide, the CFU was significantly decreased by 6 log10 after 20 J cm-2 , by 7 log10 after 30 J cm-2 irradiation, suggesting significantly higher efficacy than MB-based PDT alone. The implementation of the combination of hydrogen peroxide with MB-based PDT through working channels might be appropriate for preventing early colonization and biofilm formation in the endoscope and postendoscopy outbreak.

Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IkappaB kinase.

We previously found that bee venom (BV) and melittin (a major component of BV) has anti-inflammatory effect by reacting with the sulfhydryl group of p50 of NF-kappaB. Since the sulfhydryl group is present in IkappaB kinase (IKKalpha and IKKbeta), anti-inflammatory effect of melittin via interaction with IKKs was investigated. We first examined binding of melittin to IKKs using surface plasmon resonance analyzer. Melittin binds to IKKalpha (K(d) = 1.34 x 10(-9) M) and IKKbeta (K(d) = 1.01 x 10(-9) M). Consistent with the high binding affinity, melittin (5 and 10 microg/ml) and BV (0.5, 1 and 5 microg/ml) suppressed sodium nitroprusside, TNF-alpha and LPS induced-IKKbeta and IKKbeta activities, IkappaB release, and NF-kappaB activity as well as the expressions of iNOS and COX-2, and the generation of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in Raw 264.7 mouse macrophages and synoviocytes obtained from rheumatoid arthritis patients. The binding affinities of melittin to mutant IKKs, was reduced, and the inhibitory effect of melittin on IKK and NF-kappaB activities, and NO and PGE(2) generation were abrogated by the reducing agents or in Raw 264.7 transfected with mutant plasmid IKKalpha (C178A) or IKKbeta (C179A). These results suggest that melittin binding to the sulfhydryl group of IKKs resulted in reduced IKK activities, IkappaB release, NF-kappaB activity and generation of inflammatory mediators, indicating that IKKs may be also anti-inflammatory targets of BV.

PSMB8 and PBK as potential gastric cancer subtype-specific biomarkers associated with prognosis.

Gastric adenocarcinoma is a common form of cancer associated with a poor prognosis. We analyzed microarray profiling data from 48 patients with gastric adenocarcinoma to characterize gastric cancer subtypes and identify biomarkers associated with prognosis. We identified two major subtypes of gastric adenocarcinoma differentially associated with overall survival (P = 0.025). Genes that were differentially expressed were identified using specific criteria (P < 0.001 and >1.5-fold); expression of 294 and 116 genes was enriched in good and poor prognosis subtypes, respectively. Genes related to translational elongation and cell cycle were upregulated in the poor prognosis group. Of these genes, upregulation of proteasome subunit beta type 8 PSMB8 and PDZ binding kinase PBK was confirmed by real-time reverse transcription-PCR analysis. PSMB8 or PBK knockdown had no effect on gastric cancer cell proliferation but suppressed cell migration and invasion, respectively. Furthermore, immunohistochemistry analysis of 385 gastric cancer patients revealed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates. Taken together, two gastric adenocarcinoma subtypes were predictive of prognosis. PSMB8 and PBK were predictive of gastric cancer prognosis and could be potential gastric cancer subtype-specific biomarkers.

ER2, a novel human anti-EGFR monoclonal antibody inhibit tumor activity in non-small cell lung cancer models.

OBJECTIVES: The epidermal growth factor receptor (EGFR) abnormalities including amplification, mutation, and overexpression are frequent in non-small cell lung cancer (NSCLC). We investigated in vitro and in vivo antitumor activity of ER2, a novel human anti-EGFR monoclonal antibody, in NSCLC. METHODS: A panel of NSCLC cell lines (A549, H460, H322, H358, H1299, HCC827, PC9, H1975, and PC9-GR) was used to evaluate in vitro antitumor activity of ER2 and cetuximab. The inhibitory effects of ER2 and cetuximab on downstream signaling were assessed by western blot. Secreted VEGF was measured by Human VEGF Quantikine ELISA kit. Antitumor effects of ER2 and cetuximab as single agents and in combination with cisplatin were evaluated in H322, HCC827 and A549 xenograft models. RESULTS: ER2 efficiently inhibits EGFR and its downstream signaling molecules including Akt and Erk1/2 in NSCLC cell lines with wild-type or mutant EGFR. ER2 inhibited cell viability of H322, HCC827 and A549 cells in a dose-dependent manner by inducing cell cycle arrest and apoptosis. Also, ER2 suppressed EGF-stimulated VEGF production as efficiently as cetuximab in H322, HCC827 and A549 cells. Moreover, ER2 alone and in combination with cisplatin showed a significant anti-tumor efficacy in xenograft mouse models. CONCLUSION: Taken together, ER2 has significant anti-tumor activity in in vitro and in vivo NSCLC models, suggesting a rationale for clinical development of ER2 in NSCLC.

Snail and serpinA1 promote tumor progression and predict prognosis in colorectal cancer.

The role of Snail and serpin peptidase inhibitor clade A member 1 (serpinA1) in tumorigenesis has been previously identified. However, the exact role and mechanism of these proteins in progression of colorectal cancer (CRC) are controversial. In this study, we investigated the role of Snail and serpinA1 in colorectal cancer (CRC) and examined the mechanisms through which these proteins mediate CRC progression. Immunohistochemical analysis of 528 samples from patients with CRC showed that elevated expression of Snail or serpinA1 was correlated with advanced stage, lymph node metastasis, and poor prognosis. Moreover, we detected a correlation between Snail and serpinA1 expression. Functional studies performed using the CRC cell lines DLD-1 and SW-480 showed that overexpression of Snail or serpinA1 significantly increased CRC cell invasion and migration. Conversely, knockdown of Snail or serpinA1 expression suppressed CRC cell invasion and migration. ChIP analysis revealed that Snail regulated serpinA1 by binding to its promoter. In addition, fibronectin mediated Snail and serpinA1 signaling was involved in CRC cell invasion and migration. Taken together, our data showed that Snail and serpinA1 promoted CRC progression through fibronectin. These findings suggested that Snail and serpinA1 were novel prognostic biomarkers and candidate therapeutic targets in CRC.