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1.  Dietary Protein Sources and Incidence of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Studies 
Nutrients  2016;8(11):730.
Protein is important to the human body, and different sources of protein may have different effects on the risk of breast cancer. Thus, we conducted a meta-analysis to investigate the association between different dietary protein sources and breast cancer risk. PubMed and several databases were searched until December 2015. Relevant articles were retrieved according to specific searching criteria. Forty-six prospective studies were included. The summary relative risk (RR) for highest versus lowest intake was 1.07 (95% confidence interval (CI) 1.01–1.14, I2 = 34.6%) for processed meat, 0.92 (95% CI 0.84–1.00, I2 = 0%) for soy food, 0.93 (95% CI 0.85–1.00, I2 = 40.1%) for skim milk, and 0.90 (95% CI 0.82–1.00, I2 = 0%) for yogurt. Similar conclusions were obtained in dose-response association for each serving increase: total red meat (RR: 1.07; 95% CI 1.01–1.14, I2 = 7.1%), fresh red meat (RR: 1.13; 95% CI 1.01–1.26, I2 = 56.4%), processed meat (RR: 1.09; 95% CI 1.02–1.17, I2 = 11.8%), soy food (RR: 0.91; 95% CI 0.84–1.00, I2 = 0%), and skim milk (RR: 0.96; 95% CI 0.92–1.00, I2 = 11.9%). There was a null association between poultry, fish, egg, nuts, total milk, and whole milk intake and breast cancer risk. Higher total red meat, fresh red meat, and processed meat intake may be risk factors for breast cancer, whereas higher soy food and skim milk intake may reduce the risk of breast cancer.
PMCID: PMC5133114  PMID: 27869663
breast cancer; dietary protein sources; prospective studies; meta-analysis
2.  Protein-dependent Membrane Interaction of A Partially Disordered Protein Complex with Oleic Acid: Implications for Cancer Lipidomics 
Scientific Reports  2016;6:35015.
Bovine α-lactalbumin (BLA) forms cytotoxic complexes with oleic acid (OA) that perturbs tumor cell membranes, but molecular determinants of these membrane-interactions remain poorly understood. Here, we aim to obtain molecular insights into the interaction of BLA/BLA-OA complex with model membranes. We characterized the folding state of BLA-OA complex using tryptophan fluorescence and resolved residue-specific interactions of BLA with OA using molecular dynamics simulation. We integrated membrane-binding data using a voltage-sensitive probe and molecular dynamics (MD) to demonstrate the preferential interaction of the BLA-OA complex with negatively charged membranes. We identified amino acid residues of BLA and BLA-OA complex as determinants of these membrane interactions using MD, functionally corroborated by uptake of the corresponding α-LA peptides across tumor cell membranes. The results suggest that the α-LA component of these cytotoxic complexes confers specificity for tumor cell membranes through protein interactions that are maintained even in the lipid complex, in the presence of OA.
PMCID: PMC5059734  PMID: 27731329
3.  Urinary Tract Infection Molecular Mechanisms and Clinical Translation 
Pathogens  2016;5(1):24.
Rapid developments in infection biology create new and exciting options for individualized diagnostics and therapy. Such new practices are needed to improve patient survival and reduce morbidity. Molecular determinants of host resistance to infection are being characterized, making it possible to identify susceptible individuals and to predict their risk for future morbidity. Immunotherapy is emerging as a new strategy to treat infections worldwide and controlled boosting of the host immune defense represents an important therapeutic alternative to antibiotics. In proof of concept studies, we have demonstrated that this approach is feasible. The long-term goal is not just to remove the pathogens but to also develop technologies that restore resistance to infection in disease-prone patients and devise personalized therapeutic interventions. Here, we discuss some approaches to reaching these goals, in patients with urinary tract infection (UTI). We describe critical host signaling pathways that define symptoms and pathology and the genetic control of innate immune responses that balance protection against tissue damage. For some of these genes, human relevance has been documented in clinical studies, identifying them as potential targets for immune-modulatory therapies, as a complement to antibiotics.
PMCID: PMC4810145  PMID: 26927188
immunomodulation; genetics; innate immunity; urinary tract infection; susceptibility
4.  Time for a new language for asthma control: results from REALISE Asia 
Asthma is a global health problem, and asthma prevalence in Asia is increasing. The REcognise Asthma and LInk to Symptoms and Experience Asia study assessed patients’ perception of asthma control and attitudes toward treatment in an accessible, real-life adult Asian population.
Patients and methods
An online survey of 2,467 patients with asthma from eight Asian countries/regions, aged 18–50 years, showed greater than or equal to two prescriptions in previous 2 years and access to social media. Patients were asked about their asthma symptoms, exacerbations and treatment type, views and perceptions of asthma control, attitudes toward asthma management, and sources of asthma information.
Patients had a mean age of 34.2 (±7.4) years and were diagnosed with asthma for 12.5 (±9.7) years. Half had the Global Initiative for Asthma-defined uncontrolled asthma. During the previous year, 38% of patients visited the emergency department, 33% were hospitalized, and 73% had greater than or equal to one course of oral corticosteroids. About 90% of patients felt that their asthma was under control, 82% considered their condition as not serious, and 59% were concerned about their condition. In all, 66% of patients viewed asthma control as managing attacks and 24% saw it as an absence of or minimal symptoms. About 14% of patients who correctly identified their controller inhalers had controlled asthma compared to 6% who could not.
Patients consistently overestimated their level of asthma control contrary to what their symptoms suggest. They perceived control as management of exacerbations, reflective of a crisis-oriented mind-set. Interventions can leverage on patients’ trust in health care providers and desire for self-management via a new language to generate a paradigm shift toward symptom control and preventive care.
Video abstract
PMCID: PMC4590568  PMID: 26445555
asthma control; attitudes; perception
5.  Expression of aquaporin 5 in primary carcinoma and lymph node metastatic carcinoma of non-small cell lung cancer 
Oncology Letters  2015;9(6):2799-2804.
Aquaporin 5 (AQP5), a water channel protein, is highly expressed in non-small cell lung cancer (NSCLC) tissues compared with adjacent normal tissues. AQP5 expression in lung cancer tissues is associated with a poor prognosis. The present study aimed to analyze the expression of AQP5 and investigate its role in primary and lymph node metastatic NSCLCs. An immunohistochemical labeled streptavidin-biotin method was used to determine the expression of AQP5 in 94 cases of NSCLC primary carcinoma, which included 51 cases accompanied by lymph node metastasis. The results revealed that the expression of AQP5 was significantly higher in adenocarcinomas compared with squamous cell carcinomas (P=0.002). In addition, the percentage of AQP5 expression in the primary carcinomas with lymph node metastasis was significantly higher compared with those without lymph node metastasis (P=0.024). However, no statistically significant difference in the percentage of AQP5 expression was observed between the metastatic and the primary carcinomas (P=0.377). The expression of AQP5 exhibited a correlation with the tumor-node-metastasis staging of NSCLC (P=0.027). The percentage of AQP5 expression in stage III and IV tumors was higher than that in stage I and II tumors. In addition, AQP5 expression was correlated with the survival rate of NSCLC patients (P=0.051). In conclusion, the results of the present study provide evidence for the AQP5-facilitated incidence, progression and metastasis of NSCLC. Therefore, AQP5 may be used as a potential target to investigate the incidence, progression and metastasis of NSCLC.
PMCID: PMC4473714  PMID: 26137150
non-small cell lung cancer; aquaporin 5; primary carcinoma; lymph node metastatic carcinoma; metastasis
6.  The Effect of Tumor Microenvironment on Autophagy and Sensitivity to Targeted Therapy in EGFR-Mutated Lung Adenocarcinoma 
Journal of Cancer  2015;6(4):382-386.
Lung cancer is the top cancer killer worldwide. Tyrosine kinase inhibitors (TKIs), for example erlotinib, are commonly used to target epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC). Autophagy is a cellular response to stress, serving as a protective mechanism during anticancer therapy. The tumor microenvironment (TME) is composed of non-tumor cells that include fibroblasts. Our study aimed to investigate the effect of TME on autophagy and TKI sensitivity. Following cell sorting after direct co-culturing, autophagy and cytokine production were observed in both HCC827 and MRC-5 cells. The synergistic combination of erlotinib and chloroquine (autophagy inhibitor) was observed under TME. Tumor growth was significantly suppressed with combined erlotinib/chloroquine compared with erlotinib in HCC827 xenografts.
PMCID: PMC4349879  PMID: 25767609
Tumor microenvironment; autophagy; tyrosine kinase inhibitors; non-small cell lung carcinoma
9.  A Systematic Review and Meta-Analysis of Herbal Medicine on Chronic Obstructive Pulmonary Diseases 
Herbal medicine (HM) as an adjunct therapy has been shown to be promising for the chronic obstructive pulmonary disease (COPD). However, the role of herbs in COPD remains largely unexplored. In this present study, we conducted the systematic review to evaluate the efficacy of herbs in COPD. 176 clinical studies with reporting pulmonary function were retrieved from English and Chinese database. Commonly used herbs for acute exacerbations stage (AECOPD) and stable COPD stage (SCOPD) were identified. A meta-analysis conducted from 15 high quality studies (18 publications) showed that HM as an adjunct therapy had no significant improvement in pulmonary function (FEV1, FEV%, FVC, and FEV1/FVC) compared to conventional medicine. The efficacy of the adjunct HM on improving the arterial blood gas (PaCO2 and PaO2) for AECOPD and SCOPD remains inconclusive due to the heterogeneity among the studies. However, HM as an adjunct therapy improved clinical symptoms and quality of life (total score, activity score, and impact score of St. George's Respiratory Questionnaire). Studies with large-scale and double-blind randomized controlled trials are required to confirm the role of the adjunct HM in the management of COPD.
PMCID: PMC3984792  PMID: 24795773
10.  Sustained Elevation of Systemic Oxidative Stress and Inflammation in Exacerbation and Remission of Asthma 
ISRN Allergy  2013;2013:561831.
Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.
PMCID: PMC3773380  PMID: 24073339
11.  Treatment Outcomes in Elderly with Advanced-Stage Non-small Cell Lung Cancer 
Lung  2013;191(6):645-654.
Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome.
Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls.
Fifty-six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups
In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR–TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known.
PMCID: PMC3837186  PMID: 23929397
Lung cancer; Elderly; Treatment; Outcome
12.  The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck 
Head & Neck Oncology  2011;3:11.
We examine the potential prognostic and predictive roles of EGFR variant III mutation, EGFR gene copy number (GCN), human papillomavirus (HPV) infection, c-MET and p16INK4A protein expression in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
We analyzed the archival tumor specimens of 53 patients who were treated in 4 phase II trials for R/M SCCHN. Two trials involved the EGFR inhibitor erlotinib, and 2 trials involved non-EGFR targeted agents. EGFRvIII mutation was determined by quantitative RT-PCR, HPV DNA by Linear Array Genotyping, p16 and c-MET protein expression by immunohistochemistry, and EGFR GCN by FISH.
EGFRvIII mutation, detected in 22 patients (42%), was associated with better disease control, but no difference was seen between erlotinib-treated versus non-erlotinib treated patients. EGFRvIII was not associated with TTP or OS. The presence of HPV DNA (38%), p16 immunostaining (32%), c-MET high expression (58%) and EGFR amplification (27%), were not associated with response, TTP or OS.
EGFRvIII mutation, present in about 40% of SCCHN, appears to be an unexpected prognostic biomarker associated with better disease control in R/M SCCHN regardless of treatment with erlotinib. Larger prospective studies are required to validate its significance.
PMCID: PMC3052237  PMID: 21352589
13.  Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib 
Head & neck  2009;31(8):1006-1012.
Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib
Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib.
For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-ACC subtypes.
HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation.
PMCID: PMC2711990  PMID: 19309723
MSGT; lapatinib; EGFR and HER2 gene amplification; FISH
14.  SNAI1 expression and the mesenchymal phenotype: an immunohistochemical study performed on 46 cases of oral squamous cell carcinoma 
SNAI1 can initiate epithelial-mesenchymal transition (EMT), leading to loss of epithelial characteristics and, in cancer, to invasion and metastasis. We hypothesized that SNAI1 reactivation occurs in oral squamous cell carcinoma (OSCC) where it might also be associated with focal adhesion kinase (FAK) expression and p63 loss.
Immunohistochemistry was performed on 46 tumors and 26 corresponding lymph node metastases. Full tissue sections were examined to account for rare and focal expression. Clinical outcome data were collected and analyzed.
SNAI1-positivity (nuclear, ≥ 5% tumor cells) was observed in 10 tumors and 5 metastases (n = 12 patients). Individual SNAI1(+) tumor cells were seen in primary tumors of 30 patients. High level SNAI1 expression (>10% tumor cells) was rare, but significantly associated with poor outcome. Two cases displayed a sarcomatoid component as part of the primary tumor with SNAI1(+)/FAK(+)/E-cadherin(-)/p63(-) phenotype, but disparate phenotypes in corresponding metastases. All cases had variable SNAI1(+) stroma. A mesenchymal-like immunoprofile in primary tumors characterized by E-cadherin loss (n = 29, 63%) or high cytoplasmic FAK expression (n = 10, 22%) was associated with N(+) status and tumor recurrence/new primary, respectively.
SNAI1 is expressed, although at low levels, in a substantial proportion of OSCC. High levels of SNAI1 may herald a poor prognosis and circumscribed SNAI1 expression can indicate the presence of a sarcomatoid component. Absence of p63 in this context does not exclude squamous tumor origin. Additional EMT inducers may contribute to a mesenchymal-like phenotype and OSCC progression.
PMCID: PMC2829523  PMID: 20181105
15.  Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer 
Cancer Chemotherapy and Pharmacology  2009;65(6):1023-1028.
Chemotherapy is the mainstay treatment for advanced non-small cell lung cancer (NSCLC). Gefitinib, an epidermal growth factor receptor—tyrosine kinase inhibitor (EGFR-TKI), has been recently shown to be effective as a first-line treatment in Asian patients with advanced NSCLC, especially for those with favourable clinical features such as female, non-smoker and adenocarcinoma. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment. The purpose of this study is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib.
Retrospective review of NSCLC patients with favourable clinical features who received gefitinib as first-line treatment and subsequent salvage treatment with erlotinib.
A total of 21 patients with NSCLC were included in the study. Among them, 18 (85.7%) patients had disease control with gefitinib and 12 (57.1%) patients with salvage erlotinib. There was an association between the disease control with gefitinib and erlotinib (p = 0.031). The disease control rate of erlotinib was independent of the chemotherapy use between the two EGFR-TKIs.
For NSCLC patients with favourable clinical features, erlotinib was effective in those who had prior disease control with first-line gefitinib.
PMCID: PMC2946542  PMID: 19680652
Non-small cell lung cancer; Gefitinib; Erlotinib; Epidermal growth factor receptor tyrosine kinase inhibitors; Asians; Disease control rate
16.  Quantitative image analysis of immunohistochemical stains using a CMYK color model 
Computer image analysis techniques have decreased effects of observer biases, and increased the sensitivity and the throughput of immunohistochemistry (IHC) as a tissue-based procedure for the evaluation of diseases.
We adapted a Cyan/Magenta/Yellow/Key (CMYK) model for automated computer image analysis to quantify IHC stains in hematoxylin counterstained histological sections.
The spectral characteristics of the chromogens AEC, DAB and NovaRed as well as the counterstain hematoxylin were first determined using CMYK, Red/Green/Blue (RGB), normalized RGB and Hue/Saturation/Lightness (HSL) color models. The contrast of chromogen intensities on a 0–255 scale (24-bit image file) as well as compared to the hematoxylin counterstain was greatest using the Yellow channel of a CMYK color model, suggesting an improved sensitivity for IHC evaluation compared to other color models. An increase in activated STAT3 levels due to growth factor stimulation, quantified using the Yellow channel image analysis was associated with an increase detected by Western blotting. Two clinical image data sets were used to compare the Yellow channel automated method with observer-dependent methods. First, a quantification of DAB-labeled carbonic anhydrase IX hypoxia marker in 414 sections obtained from 138 biopsies of cervical carcinoma showed strong association between Yellow channel and positive color selection results. Second, a linear relationship was also demonstrated between Yellow intensity and visual scoring for NovaRed-labeled epidermal growth factor receptor in 256 non-small cell lung cancer biopsies.
The Yellow channel image analysis method based on a CMYK color model is independent of observer biases for threshold and positive color selection, applicable to different chromogens, tolerant of hematoxylin, sensitive to small changes in IHC intensity and is applicable to simple automation procedures. These characteristics are advantageous for both basic as well as clinical research in an unbiased, reproducible and high throughput evaluation of IHC intensity.
PMCID: PMC1810239  PMID: 17326824

Results 1-16 (16)