Non-viral factors contributing to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non-alcoholic steatohepatitis represent significant risk factors for HCC. Other non-viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, α-1 antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrastray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion,clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC.

Non-linguistic Factors and Strategies on the English-Chinese Translation of Humor

The text have an in-depth discussion of the non-linguistic factors on the English-Chinese Translation of humor,and according to different types of humor,summarized the corresponding translation strategies,including the naturalization,replacement and explanation.

Clustering of Non-communicable Diseases Risk Factors in Healthy Adults Aged 35 Years and Older in Shenzhen,China

We assessed the prevalence of non‐ communicable diseases（NCDs） risk factors with a focus on their clustering among healthy adults in Shenzhen, China. Data from the 2011 China Health and Nutrition Survey, comprising a regionally representative sample of 806 healthy adults aged 35 years or older, were obtained to determine the prevalence of five risk factors for NCDs. The prevalence of current smoking, central obesity, impaired fasting glucose, borderline hypertension, and borderline high total cholesterol was 19.97%, 28.29%, 4.47%, 10.55%, and 36.10%, respectively. A total 63.77% of participants had at least one risk factor. Upon examination of risk factor clustering, we observed that 7.57% of participants had at least three risk factors. Using this threshold as a cutoff, clustering of risk factors was associated with sex [odds ratio（OR） = 3.336, 95% confidence interval（CI）： 1.782 to 6.246], physical activity（OR = 1.913, 95% CI： 1.009 to 3.628）, and BMI（OR = 7.376, 95% CI： 3.812 to 14.270）. The prevalence of risk factors for NCDs is fairly high among healthy adults in Shenzhen, with a clustering tendency.

Prevalence of and risk factors for non-alcoholic fatty liver disease in a Chinese population: An 8-year follow-up study

AIM: To investigate the prevalence of and risk factors for non-alcoholic fatty liver disease(NAFLD) in a Chinese population.METHODS: A total of 1948 adults from China was followed for 8 years. A cross-sectional study was performed to investigate the prevalence of NAFLD at baseline, and then the participants were followed for 8 years to investigate risk factors for the development of NAFLD.RESULTS: A total of 1948 participants were enrolled at baseline, of whom 691 were diagnosed with NAFLD. During the 8-year follow-up, 337 baseline NAFLD-free participants developed NAFLD. They had a greaterincrease in body mass index(BMI), serum uric acid, fasting plasma glucose, very low-density lipoprotein cholesterol and a considerable decrease in high-density lipoprotein cholesterol. 123 participants who had NAFLD at baseline lost NAFLD during the 8-year follow-up period. They had a greater decrease in BMI, fasting plasma glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase.CONCLUSION: NAFLD is prevalent in Chinese population with a rapidly increasing tendency. It can be reversed when patients lose their weight, control their hyperlipidemia and hyperglycemia, and reduce the liver enzyme levels.

Risk factors for proton pump inhibitor refractoriness in Chinese patients with non-erosive reflux disease

AIM:To analyze risk factors for refractoriness to proton pump inhibitors(PPIs) in patients with non-erosive reflux disease(NERD).METHODS:A total of 256 NERD patients treated with the PPI esomeprazole were enrolled.They were classified into symptom-free and residual symptoms groups according to Quality of Life in Reflux and Dyspepsia(QolRad) scale.All subjects completed questionnaires on psychological status(self-rating anxiety scale;selfrating depression scale) and quality of life scale(Short Form 36).Multivariate analysis was used to determine the predictive factors for PPI responses.RESULTS:According to QolRad,97 patients were confirmed to have residual reflux symptoms,and the remaining 159 patients were considered symptom free.There were no significant differences between the two groups in lifestyle factors(smoking and alcohol consumption),age,Helicobacter pylori infection,and hiatal hernia.There were significant differences between the two groups in relation to sex,psychological distress including anxiety and depression,body mass index(BMI),and irritable bowel syndrome(IBS)(P < 0.05).Logistic regression analysis found that BMI < 23,comorbid IBS,anxiety,and depression were major risk factors for PPI resistance.Symptomatic patients had a lower quality of life compared with symptom-free patients.CONCLUSION:Some NERD patients are refractory to PPIs and have lower quality of life.Residual symptoms are associated with psychological distress,intestinal disorders,and low BMI.

Risk factors of gastroparesis syndrome after abdominal nongastroduodenal operation and its prevention

Objective:To investigate risk factors of gastroparesis syndrome(PGS) after abdominal nongastroduodenal operation and its prevention.Methods:Clinical data of 22 patients with PGS after abdominal non-gastroduodenal operation was analyzed retrospectively,and compared with the patients of non-PGS after abdominal non-gastroduodenal operation during the same time.The possible influencing factors of PCS were analyzed by single factor analysis and logistic regression analysis.Results:All t3 selected factors related with PGS,including age,disease category (benign and malignant),operation time,intraoperative blood loss,postoperative analgesic pump, postoperative enteral nutrition time,postoperative parenteral nutrition time,perioperative blood glucose level,perioperative nutrition status(anaemia or lower proleinemia),pylorus obstruction before surgery,intra-abdominal infection after surgery,and spiritual factor were related with PGS.The statistical analysis showed that the difference was statistical significant(P【0.05),and gender had no correlation with PCS(P】0.05);non-conditional multivariate analysis showed that malignant tumor,perioperative nutrition status,pylorus obstruction,operation time,blood loss, intra-abdominal infection after surgery,and mental factor were significant related with PGS as dependent variable and related risk factors in single factor analysis as independent variables (P 【0.05).Conclusions:PGS is a result of multiple factors,and among these factors,malignant tumor,poor nutrition status,pylorus obstruction before surgery,longer operation—time,more blood loss,intra-abdominal infection after surgery,and mental factor are major risk factors of PGS.

Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis

AIM The impact of mild drinking habit(less than 20 g/d of ethanol) on the clinical course of non-alcoholic fatty liver disease(NAFLD) has not been determined. We examined the influence of a mild drinking habit on liver carcinogenesis from NAFLD. METHODS A total of 301 patients who had been diagnosed as having NAFLD by liver biopsy between 2003 and 2016 [median age: 56 years, 45% male, 56% with nonalcoholic steatohepatitis, 26% with advanced fibrosis(F3-4)] were divided into the mild drinking group withe thanol consumption of less than 20 g/d(mild drinking group, n = 93) and the non-drinking group(n = 208). Clinicopathological features at the time of liver biopsy and factors related to hepatocellular carcinoma(HCC) occurrence were compared between the groups.RESULTS We observed significant differences in male prevalence(P = 0.01), platelet count(P = 0.04), and gammaglutamyl transpeptidase(P = 0.02) between the test groups. Over 6 years of observation, the HCC appearance rate was significantly higher in the mild drinking group(6.5% vs 1.4%, P = 0.02). Multivariate survival analysis using Cox's regression model revealed that hepatic advanced fibrosis(F3-4)(P < 0.01, risk ratio: 11.60), diabetes mellitus(P < 0.01, risk ratio: 89.50), and serum triglyceride(P = 0.04, risk ratio: 0.98) were factors significantly related to HCC in all NAFLD patients, while the effect of a drinking habit was marginal(P = 0.07, risk ratio: 4.43). In patients with advanced fibrosis(F3-4), however, a drinking habit(P = 0.04, risk ratio: 4.83), alpha-fetoprotein(P = 0.01, risk ratio: 1.23), and diabetes mellitus(P = 0.03, risk ratio: 12.00) were identified as significant contributors to HCC occurrence. CONCLUSION A mild drinking habit appears to be a risk factor for hepatocarcinogenesis in NAFLD patients, especially those with advanced fibrosis.

New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs

Helicobacter pylori(H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, Micro RNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.

Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis:Paving the way to hepatocellular carcinoma

Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for(non-liver)cancer therapy,treatment of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis is still limited.Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.

Feature Extraction and Recognition for Rolling Element Bearing Fault Utilizing Short-Time Fourier Transform and Non-negative Matrix Factorization

Due to the non-stationary characteristics of vibration signals acquired from rolling element bearing fault, thc time-frequency analysis is often applied to describe the local information of these unstable signals smartly. However, it is difficult to classitythe high dimensional feature matrix directly because of too large dimensions for many classifiers. This paper combines the concepts of time-frequency distribution（TFD） with non-negative matrix factorization（NMF）, and proposes a novel TFD matrix factorization method to enhance representation and identification of bearing fault. Throughout this method, the TFD of a vibration signal is firstly accomplished to describe the localized faults with short-time Fourier transform（STFT）. Then, the supervised NMF mapping is adopted to extract the fault features from TFD. Meanwhile, the fault samples can be clustered and recognized automatically by using the clustering property of NMF. The proposed method takes advantages of the NMF in the parts-based representation and the adaptive clustering. The localized fault features of interest can be extracted as well. To evaluate the performance of the proposed method, the 9 kinds of the bearing fault on a test bench is performed. The proposed method can effectively identify the fault severity and different fault types. Moreover, in comparison with the artificial neural network（ANN）, NMF yields 99.3% mean accuracy which is much superior to ANN. This research presents a simple and practical resolution for the fault diagnosis problem of rolling element bearing in high dimensional feature space.

Expression of Nerve Growth Factor and Hypoxia Inducible Factor-1α and Its Correlation with Angiogenesis in Non-Small Cell Lung Cancer

Summary： In order to investigate the expression of nerve growth factor （NGF） and hypoxia inducible factor-1α （HIF-1α） and its correlation with angiogenesis in non-small cell lung cancer （NSCLC）, paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor （VEGF） in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density （MVD） was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues （P〈0.05）. There was significant difference in the MVD between the NSCLC tissues （9.19±1.43） and para-cancerous lung tissues （2.23±1.19） （P〈0.05）. There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors （P〈0.05）. Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

Graph Regularized L_p Smooth Non-negative Matrix Factorization for Data Representation

This paper proposes a Graph regularized Lpsmooth non-negative matrix factorization(GSNMF) method by incorporating graph regularization and L_p smoothing constraint, which considers the intrinsic geometric information of a data set and produces smooth and stable solutions. The main contributions are as follows: first, graph regularization is added into NMF to discover the hidden semantics and simultaneously respect the intrinsic geometric structure information of a data set. Second,the Lpsmoothing constraint is incorporated into NMF to combine the merits of isotropic(L_2-norm) and anisotropic(L_1-norm)diffusion smoothing, and produces a smooth and more accurate solution to the optimization problem. Finally, the update rules and proof of convergence of GSNMF are given. Experiments on several data sets show that the proposed method outperforms related state-of-the-art methods.

Correlation between non-alcoholic fatty liver with metabolic risk factors and brachial-ankle pulse wave velocity

AIM: To assess the relationship between non-alcoholic fatty liver disease(NAFLD) with metabolic risk factors and brachial ankle pulse wave velocity(ba PWV). METHODS: A total of 8603 subjects(6662 males and 1941 females) were enrolled during an annual health check-up. Fatty liver was examined using a Philips HD 11 XE multi-function color Doppler diagnostic instrument, and ba PWV was determined using a novel arteriosclerosis detection device. Blood pressure(BP), fasting plasma glucose(FPG), waist circumference( W C), p l a s m a t r i g l y c e r i d e s( TG), h i g h- d e n s i t y lipoprotein(HDL), total cholesterol(TC), low-density lipoprotein(LDL) and uric acid(UA) were measured using standard methods. The relationship between fatty liver with metabolic risk factors and ba PWV was analyzed using regression analysis and the χ2 test. RESULTS: The values and abnormal rates of ba PWV were significantly different between NAFLD patients and non-NAFLD subjects(P < 0.001). In addition, the values of ba PWV were different by gender between NAFLD patients and non-NAFLD subjects. The OR values in females, males, and the entire population were 3.33, 1.67, and 2.13, respectively(P < 0.001). The incidence of high ba PWV increased with increasing degree of NAFLD(levels 0, 1, 2, and 3)(P < 0.001), which was 45.9%, 54.5%, 60.2%, and 71.4% in malesand 27.0%, 49.1%, 55.60%, and 60.0% in females(P < 0.001), respectively. Logistic regression analysis showed that the OR value for ba PWV in the nonmetabolic syndrome group and the metabolic syndrome group was 1.28 vs 1.14(males) and 2.55 vs 0.98(females). The OR values for ba PWV in the non-high-BP and high-BP, non-high-WC and high-WC, non-high-FPG and high-FPG, non-high-TG and high-TG, non-high-HDL and high-HDL, non-high-TC and high-TC, non-high-LDL and high-LDL, non-high-UA and high-UA groups were 3.38 vs 1.19, 3.50 vs 1.44, 2.80 vs 2.30, 3.29 vs 1.88, 3.03 vs 3.28, 3.35 vs 2.70, 3.93 vs 1.66, and 3.20 vs 2.34, respectively, in females(P < 0.001), and were 1.37 vs 1.34, 1.56 vs 1.26, 1.51 vs 1.28, 1.49 vs 1.52, 1.71 vs 1.61, 1.59 vs 1.74, 1.76 vs 1.47, and 1.73 vs 1.54, respectively, in males(P < 0.01). The OR value for ba PWV was still higher than 1.2(1.21 in males and 1.40 in females) after adjustment for the metabolic component(0, 1, 2, 3, 4, 5, 6 and above)(P < 0.01).CONCLUSION: NAFLD is closely correlated with ba PWV, particularly in females. NAFLD has a large impact on ba PWV, no matter whether the metabolic index is increased or not. NAFLD may be a useful indicator for assessing early arteriosclerosis.

Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy

Background: Locoregional recurrence remains the challenge for long-term survival of non-small cell lung cancer(NSCLC) patients after radical surgery, and curative-intent radiotherapy could be a treatment choice. This study aimed to assess the survival and prognostic factors of patients with postoperative locoregionally recurrent NSCLC treated with radical radiotherapy.Methods: We reviewed medical records of 74 NSCLC patients with postoperative locoregional recurrence who received radical radiotherapy between April 2012 and February 2016 at Sun Yat-sen University Cancer Center(Guangzhou, China). The efficacy and safety of radical radiotherapy were analyzed. The probability of survival was estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to identify prognostic factors.Results: Grade 3/4 adverse events included neutropenia(8 cases, 10.8%), esophagitis(7 cases, 9.5%), pneumonitis(1 case, 1.4%), and vomiting(1 case, 1.4%).The 2-year overall survival, progression-free survival, local recurrencefree survival(LRFS), and distant metastasis-free survival(DMFS) rates of all patients were 84.2,42.5,70.0, and 50.9%,respectively. Univariate and multivariate analyses showed that a higher biological effective dose(BED) of radiation was associated with longer LRFS [hazard ratios(HR)=0.317,95% confidence interval(CI) = 0.112-0.899, P = 0.016] and that wild-type epidermal growth factor receptor(EGFR) was associated with longer DMFS compared with EGFR mutation(HR = 0.383,95% CI=0.171-0.855, P = 0.019).Conclusions: Radical radiotherapy is effective and well-tolerated in NSCLC patients with postoperative locoregional recurrence. High BED is a predictor for long LRFS, and the presence of wild-type EGFR is a predictor for long DMFS.

Effects of Size Grading on Growth and Non-Specific Immunity Factors of the Shrimp Litopenaeus vannamei Boone

The study aims to determine the effects of graded farming on growth performance and non-specific immunity factors of shrimp Litopenaeus vannamei Boone. Three size groups of shrimp, i.e., the small size group [Gs, with an average body length （BL） of （3.04 ± 0.36） cm and body weight （BW） （0.412± 0.35） g], the large group [GL, with a BL of （4.29±0.55） cm and BW of （1.098 ±0.42） g], and the ungraded group [Gm, with a BL of （3.47±0.81） cm and BW of （0.611 ±0.79） g], were reared under the same conditions for 8 wk. Growth performance and non- specific immunity factors were measured. The results showed that BW gain, biomass gain and the specific growth rate of body length （SGRL） were significantly influenced by size grading （one-way ANOVA, P 〈 0.05）. The peroxidase （POD） and antibacterial （Ua） activities of GL were lower than those of G. Superoxide dismutase （SOD） and lysozyme （U1） activities of Gm were lower than those of G. No significant difference （P = 0.121 〉 0.05） was found on phenoloxidase （PO） activity among the three size groups. Synthetically, size grading could enhance growth and rearing efficiency, and did not have a significant influence on the immunity of L. vannamei Boone. Therefore, graded fanning in L. vannamei Boone was feasible in the culture practice.

Obtaining Profiles Based on Localized Non-negative Matrix Factorization

Nonnegative matrix factorization (NMF) is a method to get parts-based features of information and form the typical profiles. But the basis vectors NMF gets are not orthogonal so that parts-based features of information are usually redundancy. In this paper, we propose two different approaches based on localized non-negative matrix factorization (LNMF) to obtain the typical user session profiles and typical semantic profiles of junk mails. The LNMF get basis vectors as orthogonal as possible so that it can get accurate profiles. The experiments show that the approach based on LNMF can obtain better profiles than the approach based on NMF. Key words localized non-negative matrix factorization - profile - log mining - mail filtering CLC number TP 391 Foundation item: Supported by the National Natural Science Foundation of China (60373066, 60303024), National Grand Fundamental Research 973 Program of China (2002CB312000), National Research Foundation for the Doctoral Program of Higher Education of China (20020286004).Biography: Jiang Ji-xiang (1980-), male, Master candidate, research direction: data mining, knowledge representation on the Web.

Zinc-α2-glycoprotein 1 attenuates non-alcoholic fatty liver disease by negatively regulating tumour necrosis factor-α

BACKGROUND Zinc-α2-glycoprotein 1 (AZGP1) plays important roles in metabolism-related diseases. The underlying molecular mechanisms and therapeutic effects of AZGP1 remain unknown in non-alcoholic fatty liver disease (NAFLD). AIM To explore the effects and potential mechanism of AZGP1 on NAFLD in vivo and in vitro. METHODS The expression of AZGP1 and its effects on hepatocytes were examined in NAFLD patients, CCl4-treated mice fed a high fat diet (HFD), and human LO2 cells. RESULTS AZGP1 levels were significantly decreased in liver tissues of NAFLD patients and mice. AZGP1 knockdown was found to activate inflammation;enhance steatogenesis, including promoting lipogenesis [sterol regulatory elementbinding protein (SREBP)-1c, liver X receptor (LXR), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl CoA desaturase 1 (SCD)-1], increasing lipid transport and accumulation [fatty acid transport protein (FATP), carnitine palmitoyl transferase (CPT)-1A, and adiponectin], and reducing fatty acid β-oxidation [farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)-α];accelerate proliferation;and reverse apoptosis in LO2 cells. AZGP1 overexpression (OV-AZGP1) had the opposite effects. Furthermore, AZGP1 alleviated NAFLD by blocking TNF-α-mediated inflammation and intracellular lipid deposition, promoting proliferation, and inhibiting apoptosis in LO2 cells. Finally, treatment with OV-AZGP1 plasmid dramatically improved liver injury and eliminated liver fat in NAFLD mice. CONCLUSION AZGP1 attenuates NAFLD with regard to ameliorating inflammation, accelerating lipolysis, promoting proliferation, and reducing apoptosis by negatively regulating TNF-α. AZGP1 is suggested to be a novel promising therapeutic target for NAFLD.

Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants

Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy.

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer(NSCLC)

Purpose： A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） in advanced non-small-cell lung cancer （NSCLC）. This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. Patients and methods： EGFR gene typing in 33 advanced NSCLC patients received gefitinib （250 mg/day） were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. Results： The overall objective response rate （ORR） and median progression-flee survival （PFS） in the 33 patients treated by gefitinib were 45.5% and 3.0 （2.0-4.0） months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients （P〈0.01）. Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients （P〈0.05, P〈0.01, respectively）. However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR （P〈0.01）. Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS （P〈0.05）. Conclusions： EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.