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1.  Reduced Occurrence of Tumor Flare with Flavopiridol Followed by Combined Flavopiridol and Lenalidomidein Patients with Relapsed Chronic Lymphocytic Leukemia (CLL) 
American journal of hematology  2015;90(4):327-333.
Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg/m2 intravenous bolus (IVB) + 30 mg/m2 continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg/m2 IVB + 50 mg/m2 CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.
doi:10.1002/ajh.23946
PMCID: PMC4552311  PMID: 25639448
chronic lymphocytic leukemia; flavopiridol; lenalidomide; tumor flare; tumor lysis mitochondrial profiling
2.  A comment on sample size calculations for binomial confidence intervals 
Journal of applied statistics  2012;40(2):311-319.
In this article we examine sample size calculations for a binomial proportion based on the confidence interval width of the Agresti–Coull, Wald and Wilson Score intervals. We pointed out that the commonly used methods based on known and fixed standard errors cannot guarantee the desired confidence interval width given a hypothesized proportion. Therefore, a new adjusted sample size calculation method was introduced, which is based on the conditional expectation of the width of the confidence interval given the hypothesized proportion. With the reduced sample size, the coverage probability can still maintain at the nominal level and is very competitive to the converge probability for the original sample size.
doi:10.1080/02664763.2012.740629
PMCID: PMC4792103  PMID: 26989292
binomial proportion; sample size calculation; expected width; Agresti—Coull interval; Wald interval; Wilson Score interval
3.  An Investigation of Quantile Function Estimators Relative to Quantile Confidence Interval Coverage 
In this article, we investigate the limitations of traditional quantile function estimators and introduce a new class of quantile function estimators, namely, the semi-parametric tail-extrapolated quantile estimators, which has excellent performance for estimating the extreme tails with finite sample sizes. The smoothed bootstrap and direct density estimation via the characteristic function methods are developed for the estimation of confidence intervals. Through a comprehensive simulation study to compare the confidence interval estimations of various quantile estimators, we discuss the preferred quantile estimator in conjunction with the confidence interval estimation method to use under different circumstances. Data examples are given to illustrate the superiority of the semi-parametric tail-extrapolated quantile estimators. The new class of quantile estimators is obtained by slight modification of traditional quantile estimators, and therefore, should be specifically appealing to researchers in estimating the extreme tails.
doi:10.1080/03610926.2013.775304
PMCID: PMC4768491  PMID: 26924881
Characteristic function; Direct density estimation; Inversion theorem; Smoothed bootstrap; Tail extrapolation
4.  Pre-operative prediction of surgical morbidity in children: comparison of five statistical models 
Background
The accurate prediction of surgical risk is important to patients and physicians. Logistic regression (LR) models are typically used to estimate these risks. However, in the fields of data mining and machine-learning, many alternative classification and prediction algorithms have been developed. This study aimed to compare the performance of LR to several data mining algorithms for predicting 30-day surgical morbidity in children.
Methods
We used the 2012 National Surgical Quality Improvement Program-Pediatric dataset to compare the performance of 1) a LR model that assumed linearity and additivity (simple LR model) 2) a LR model incorporating restricted cubic splines and interactions (flexible LR model) 3) a support vector machine, 4) a random forest and 5) boosted classification trees for predicting surgical morbidity.
Results
The ensemble-based methods showed significantly higher accuracy, sensitivity, specificity, PPV, and NPV than the simple LR model. However, none of the models performed better than the flexible LR model in terms of the aforementioned measures or in model calibration or discrimination.
Conclusion
Support vector machines, random forests, and boosted classification trees do not show better performance than LR for predicting pediatric surgical morbidity. After further validation, the flexible LR model derived in this study could be used to assist with clinical decision-making based on patient-specific surgical risks.
doi:10.1016/j.compbiomed.2014.11.009
PMCID: PMC4306609  PMID: 25528697
data mining; machine learning; prediction; boosting; random forests; support vector machines; logistic regression; surgical morbidity; pediatrics
5.  Deep sequencing of hepatitis B virus basal core promoter and precore mutants in HBeAg-positive chronic hepatitis B patients 
Scientific Reports  2015;5:17950.
Mutants in the basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) genome are associated with the progression of chronic hepatitis B (CHB) infection. However, quasispecies characteristics of naturally occurring mutants in those regions in HBeAg-positive CHB patients has not been well described, partly limited by quantitative assay. This study aimed to develop an Ion Torrent deep sequencing assay to determine BCP and PC mutant percentages in HBeAg-positive CHB patients who were treatment naïve and correlate them with different viral and host factors. Our results showed that Ion Torrent deep sequencing could achieve high accuracy (R2>0.99) within a dynamic range between 1% and 100%. Twelve hotspots with prevalence of greater than 20% were observed in EnhII/BCP/PC regions. G1719T, T1753V, A1762T and G1764A were genotype C related. BCP A1762T/G1764A double mutants were generally accompanied with PC 1896 wild type or lower PC G1896A mutant percentage. Lower serum HBeAg and HBsAg levels were associated with higher BCP A1762T/G1764A mutant percentages (≥50%). ALT levels were higher in patients with PC G1896A mutant percentage greater than 10%. In conclusion, deep sequencing such as Ion Torrent sequencing could accurately quantify HBV mutants for providing clinical relevant information during HBV infection.
doi:10.1038/srep17950
PMCID: PMC4673698  PMID: 26647737
6.  Delivery of cell-penetrating peptide-peptide nucleic acid conjugates by assembly on an oligonucleotide scaffold 
Scientific Reports  2015;5:17640.
Delivery to intracellular target sites is still one of the main obstacles in the development of peptide nucleic acids (PNAs) as antisense-antigene therapeutics. Here, we designed a self-assembled oligonucleotide scaffold that included a central complementary region for self-assembly and lateral regions complementing the PNAs. Assembly of cell-penetrating peptide (CPP)-PNAs on the scaffold significantly promoted endocytosis of PNAs by at least 10-fold in cell cultures, particularly for scaffolds in which the central complementary region was assembled by poly(guanine) and poly(cytosine). The antisense activity of CPP-PNAs increased by assembly on the scaffold and was further enhanced after co-assembly with endosomolytic peptide (EP)-PNA. This synergistic effect was also observed following the assembly of antigene CPP-PNAs\EP-PNAs on the scaffold. However, antigene activity was only observed by targeting episomal viral DNA or transfected plasmids, but not the chromosome in the cell cultures. In conclusion, assembly on oligonucleotide scaffolds significantly enhanced the antisense-antigene activity of PNAs by promoting endocytosis and endosomal escape. This oligonucleotide scaffold provided a simple strategy for assembly of multiple functional peptide-PNA conjugates, expanding the applications of PNAs and demonstrating the potential of PNAs as antiviral therapeutics.
doi:10.1038/srep17640
PMCID: PMC4661726  PMID: 26612536
7.  Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma 
Background
PD-L1 expression on neutrophils contributes to the impaired immune response in infectious disease, but the detailed role of PD-L1 expression on neutrophils in HCC remains unclear.
Methods
We investigated the phenotype and morphology of neutrophils infiltrated in tumour tissues from both patients with HCC and hepatoma-bearing mice.
Results
We found that neutrophils dominantly infiltrated in the peritumoural region. The neutrophil-to-T cell ratio (NLR) was higher in peritumoural tissue than that in the intratumoural tissue and was negatively correlated with the overall survival of patients with HCC. Infiltrating neutrophils displayed a phenotype of higher frequency of programmed cell death ligand 1 (PD-L1) positive neutrophils. The ratio of PD-L1+ neutrophils-to-PD-1+ T cells was higher in peritumoural tissue and better predicted the disease-free survival of patients with HCC. We further confirmed a higher frequency of PD-L1+ neutrophils and PD-1+ T cells in hepatoma-bearing mice. Functionally, the PD-L1+ neutrophils from patients with HCC effectively suppressed the proliferation and activation of T cells, which could be partially reversed by the blockade of PD-L1.
Conclusions
Our results indicate that the tumour microenvironment induces impaired antitumour immunity via the modulation of PD-L1 expression on tumour infiltrating neutrophils.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0256-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-015-0256-0
PMCID: PMC4652417  PMID: 26581194
Neutrophils; Hepatocellular carcinoma; Predictive Value; Programmed death ligand 1
8.  Quasi suppression of higher-order diffractions with inclined rectangular apertures gratings 
Scientific Reports  2015;5:16502.
Advances in the fundamentals and applications of diffraction gratings have received much attention. However, conventional diffraction gratings often suffer from higher-order diffraction contamination. Here, we introduce a simple and compact single optical element, named inclined rectangular aperture gratings (IRAG), for quasi suppression of higher-order diffractions. We show, both in the visible light and soft x-ray regions, that IRAG can significantly suppress higher-order diffractions with moderate diffraction efficiency. Especially, as no support strut is needed to maintain the free-standing patterns, the IRAG is highly advantageous to the extreme-ultraviolet and soft x-ray regions. The diffraction efficiency of the IRAG and the influences of fabrication constraints are also discussed. The unique quasi-single order diffraction properties of IRAG may open the door to a wide range of photonic applications.
doi:10.1038/srep16502
PMCID: PMC4643229  PMID: 26563588
9.  Antibodies Targeting Novel Neutralizing Epitopes of Hepatitis C Virus Glycoprotein Preclude Genotype 2 Virus Infection 
PLoS ONE  2015;10(9):e0138756.
Currently, there is no effective vaccine to prevent hepatitis C virus (HCV) infection, partly due to our insufficient understanding of the virus glycoprotein immunology. Most neutralizing antibodies (nAbs) were identified using glycoprotein immunogens, such as recombinant E1E2, HCV pseudoparticles or cell culture derived HCV. However, the fact that in the HCV acute infection phase, only a small proportion of patients are self-resolved accompanied with the emergence of nAbs, indicates the limited immunogenicity of glycoprotein itself to induce effective antibodies against a highly evolved virus. Secondly, in previous reports, the immunogen sequence was mostly the genotype of the 1a H77 strain. Rarely, other genotypes/subtypes have been studied, although theoretically one genotype/subtype immunogen is able to induce cross-genotype neutralizing antibodies. To overcome these drawbacks and find potential novel neutralizing epitopes, 57 overlapping peptides encompassing the full-length glycoprotein E1E2 of subtype 1b were synthesized to immunize BALB/c mice, and the neutralizing reactive of the induced antisera against HCVpp genotypes 1–6 was determined. We defined a domain comprising amino acids (aa) 192–221, 232–251, 262–281 and 292–331 of E1, and 421–543, 564–583, 594–618 and 634–673 of E2, as the neutralizing regions of HCV glycoprotein. Peptides PUHI26 (aa 444–463) and PUHI45 (aa 604–618)-induced antisera displayed the most potent broad neutralizing reactive. Two monoclonal antibodies recognizing the PUHI26 and PUHI45 epitopes efficiently precluded genotype 2 viral (HCVcc JFH and J6 strains) infection, but they did not neutralize other genotypes. Our study mapped a neutralizing epitope region of HCV glycoprotein using a novel immunization strategy, and identified two monoclonal antibodies effective in preventing genotype 2 virus infection.
doi:10.1371/journal.pone.0138756
PMCID: PMC4583415  PMID: 26406225
10.  Upfront molecular testing in patients with advanced gastro-esophageal cancer: Is it time yet? 
Oncotarget  2015;6(26):22206-22213.
Introduction
Targeting HER2 has improved outcomes in metastatic GE (mGE) cancer. In this study, we aim to explore the feasibility of molecular profiling in patients with refractory mGE cancer in routine clinical practice.
Methods
Archival formalin-fixed, paraffin-embedded (FFPE) samples for patients with mGE were analyzed with commercially available targeted next generation sequencing (NGS) and/or FISH for MET amplification. We also reviewed the patients' medical records for concurrent HER 2 testing.
Results
Tumor samples from 99 patients with mGE cancer were analyzed as follows: NGS (N = 56), FISH for MET amplification (N = 65), IHC and/or FISH for HER2 (N = 87). Of patients who underwent NGS, 50/56 (89%) had at least one actionable molecular alteration. The most notable actionable alterations included cell cycle abnormalities (58%), HER2 amplification (30%), PI3KCA mutation (14%), MCL1 amplification (11%), PTEN loss (9%), CDH1 mutation (2%) and MET amplification (5%). Ninety-two percent (12/13) of patients with HER2 amplification by NGS were positive for HER2 by IHC and/or FISH. In contrast, only 12/18 (66%) patients positive for HER2 by IHC and/or FISH demonstrated HER2 amplification by NGS.
Conclusion
Comprehensive molecular testing is feasible in clinical practice and provides a platform for screening patients for molecularly guided clinical trials and available targeted therapies.
PMCID: PMC4673157  PMID: 26082439
next generation sequencing; gastro-esophageal cancer; molecular profiling; c-MET; targeted therapy
11.  Long-Term Telbivudine Treatment Results in Resolution of Liver Inflammation and Fibrosis in Patients with Chronic Hepatitis B 
Advances in Therapy  2015;32(8):727-741.
Introduction
The long-term goal of chronic hepatitis B (CHB) treatment is improvement of liver disease and prevention of cirrhosis. The aim of this study was to assess whether prolonged telbivudine treatment improves liver inflammation and fibrosis. The primary objective was to evaluate the proportion of patients with absence/minimal inflammation (Knodell necroinflammatory score ≤3) on liver biopsy at Year 5.
Methods
Fifty-seven patients aged 16–70 years with a clinical history of CHB and active viral replication (38 hepatitis B e antigen [HBeAg] positive and 19 HBeAg negative) were followed for 6 years: 33 received telbivudine 600 mg/day continuously for 5 years; 24 received lamivudine 100 mg/day for 2 years and then telbivudine for 3 years. Liver biopsies were taken pre-treatment and after 5 years of treatment.
Results
At baseline, mean (standard deviation) serum hepatitis B virus (HBV) DNA load was 8.5 (1.7) log10 copies/mL, Knodell necroinflammatory score was 7.6 (2.9), and Ishak fibrosis score was 2.2 (1.1). After antiviral treatment (median duration: 261 weeks), liver histology improved with increased proportions of patients with absence/minimal liver inflammation (Knodell necroinflammatory score ≤3), from 16% (9/57) at baseline to 98% (56/57), and absence/minimal fibrosis (Ishak score ≤1), from 25% (14/57) at baseline to 84% (48/57). At Year 5, HBV DNA load was <300 copies/mL for all patients; cumulative HBeAg loss and seroconversion rates were 88% and 77%, respectively. At Year 6, 95% of patients with abnormal baseline glomerular filtration rate (60–90 mL/min/1.73 m2) improved to normal GFR (>90 mL/min/1.73 m2).
Conclusion
Long-term telbivudine treatment with profound and durable viral suppression significantly improved liver histology, thus achieving the long-term goals of CHB treatment. FibroScan® results after 5 and 6 years of treatment (in almost 20% of patients) were consistent with this information.
Funding
Novartis and National Science and Technology Major Project (2012ZX10002003).
Trial registration
ClinicalTrials.gov # NCT00877149.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-015-0232-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-015-0232-2
PMCID: PMC4572721  PMID: 26329749
Chronic hepatitis B; Ishak fibrosis score; Knodell necroinflammatory score; Liver biopsy; Telbivudine
12.  Phylogenetic Relationships and Evolution of the Androecia in Ruteae (Rutaceae) 
PLoS ONE  2015;10(9):e0137190.
Ruta, which belongs to tribe Ruteae, is the type genus of the subfamily Rutoideae and the family Rutaceae. Molecular systematic studies have shown that the genera in Ruteae are closer related to Aurantioideae than to most other genera of Rutoideae, some of the genera traditionally placed in Ruteae have been shown to be nested within the Aurantioideae clade, but the diagnostic characters for determining new patterns in the relationship are poor. In this study, we investigated the floral development of Boenninghausenia in Ruteae (sensu stricto), Haplophyllum in the basal position of Aurantioideae and Murraya in traditional Aurantioideae using scanning electron microscopy. The androecium of Boenninghausenia is obdiplostemony. As androecia in other genera within Ruteae (s.s.) are also obdiplostemonous, reconstruction of the ancestral state indicates that obdiplostemony is an ancestral character in this clade. Because the androecia of Haplophyllum and Murraya are also obdiplostemonous, obdiplostemony is also an ancestral character in Aurantioideae clade. The ancestral state reconstruction indicates this character can serve as a synapomorphy of the Ruteae-Aurantioideae clade. The results of our work also shed light on the evolution of the androecium in Rutaceae, as the obdiplostemony of this group is clearly derived from haplostemony in the ancestral genera in Rutaceae and has develop into polyandry by increasing antepetalous stamens.
doi:10.1371/journal.pone.0137190
PMCID: PMC4557828  PMID: 26332986
13.  Erlotinib in African Americans with Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Study with Genetic and Pharmacokinetic Analysis 
Prospective studies focusing on EGFR inhibitors in African Americans with NSCLC have not been previously performed. In this phase II randomized study, 55 African Americans with NSCLC received erlotinib 150mg/day or a body weight adjusted dose with subsequent escalations to the maximum allowable, 200mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower compared to previous reports, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics revealed only two EGFR mutations, EGFR amplification in 17/47 samples, 8 KRAS mutations and 5 EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Observed low incidence of toxicity and low erlotinib exposure suggest standardized and maximum allowable dosing may be suboptimal in African Americans.
doi:10.1038/clpt.2014.93
PMCID: PMC4180036  PMID: 24781527
EGFR; Erlotinib; African American; Pharmacokinetics; Pharmacogenetics
14.  Prediction of chemotherapeutic response in bladder cancer using k-means clustering of DCE-MRI pharmacokinetic parameters 
Purpose
To apply k-means clustering of two pharmacokinetic parameters derived from 3T DCE-MRI to predict chemotherapeutic response in bladder cancer at the mid-cycle time-point.
Materials and Methods
With the pre-determined number of 3 clusters, k-means clustering was performed on non-dimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor’s chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer.
Results
k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value.
Conclusion
k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor’s chemotherapeutic response.
doi:10.1002/jmri.24663
PMCID: PMC4298475  PMID: 24943272
bladder cancer; chemotherapeutic response; k-means clustering; pharmacokinetic parameters
15.  STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus 
Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.
doi:10.1128/AAC.04321-14
PMCID: PMC4335851  PMID: 25512416
16.  Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease 
Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor-derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 ± 1.12 vs. 5.14 ± 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status ≥2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients.
doi:10.1007/s00262-014-1618-8
PMCID: PMC4504424  PMID: 25305035
MDSC; Pancreas cancer; Cytokines; Progression
17.  Immune Responses in Age Related Macular Degeneration and a possible Long Term Therapeutic Strategy for Prevention 
American journal of ophthalmology  2014;158(1):5-11.e2.
Purpose
To describe the immune alterations associated with, age related macular degeneration (AMD). Based on these findings, to offer an approach to possibly prevent the expression of late disease.
Design
Perspective
Methods
Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients.
Results
Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin-17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occurs throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed immunotherapy has been shown to affect the late stages of AMD.
Conclusion
Immune dysregulation appears to be an underlying alteration in AMD as in other diseases thought to be degenerative and due to aging. Parainflammation and immunosensescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin-17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression.
doi:10.1016/j.ajo.2014.03.014
PMCID: PMC4058353  PMID: 24709810
Age related macular degeneration; oral tolerance; Epigenetics; acquired and innate immunity
18.  An interferon-beta promoter reporter assay for high throughput identification of compounds against multiple RNA viruses 
Antiviral research  2014;107:56-65.
Virus infection of host cells is sensed by innate pattern recognition receptors (PRRs) and induces production of type I interferons (IFNs) and other inflammatory cytokines. These cytokines orchestrate the elimination of the viruses but are occasionally detrimental to the hosts. The outcomes and pathogenesis of viral infection are largely determined by the specific interaction between the viruses and their host cells. Therefore, compounds that either inhibit viral infection or modulate virus-induced cytokine response should be considered as candidates for managing virus infection. The aim of the study was to identify compounds in both categories, using a single cell-based assay. Our screening platform is a HEK293 cell-based reporter assay where the expression of a firefly luciferase is under the control of a human IFN-β promoter. We have demonstrated that infection of the reporter cell line with a panel of RNA viruses activated the reporter gene expression that correlates quantitatively with the levels of virus replication and progeny virus production, and could be inhibited in a dose-dependent manner by known antiviral compound or inhibitors of PRR signal transduction pathways. Using Dengue virus as an example, a pilot screening of a small molecule library consisting of 26,900 compounds proved the concept that the IFN-β promoter reporter assay can serve as a convenient high throughput screening platform for simultaneous discovery of antiviral and innate immune response modulating compounds. A representative antiviral compound from the pilot screening, 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(3-methoxyphenyl) urea, was demonstrated to specifically inhibit several viruses belonging to the family of flaviviridae.
doi:10.1016/j.antiviral.2014.04.010
PMCID: PMC4143146  PMID: 24792753
high throughput assay; antiviral; innate immune modulator; dengue virus
19.  Upper and Lower Esophageal Sphincter Kinetics are Modified During Maturation: Effect of Pharyngeal Stimulus in Premature Infants 
Pediatric research  2014;77(0):99-106.
Background
We hypothesized that changes in proximal and distal esophageal sphincter kinetics evoked upon pharyngeal provocation undergo longitudinal maturation.
Methods
Pharyngeal stimulation-induced reflexes were characterized using novel pharyngoesophageal motility methods in 19 healthy premature neonates, studied at 34.7 ± 0.8 wks (time-1), and 39.3 ± 1.1 wks postmenstrual age (time-2). Graded volumes of air (290 infusions) and sterile water (172 infusions) were infused to define sensory-motor characteristics of upstream (pharyngeal reflexive swallow, PRS) and downstream (pharyngo-lower esophageal sphincter relaxation reflex, PLESRR) esophageal reflexes. Data displayed as mean ± SE.
Results
Threshold volumes were similar with air and water for PRS and PLESRR at time-1 and time-2. Multiple PRS responses were noted with water stimulus, and were different between the media (time-1 vs. air, P< 0.0001; time-2 vs. air, P =0.0003). Dose response relationships for water were significant (P<0.01 for PRS and PLESRR time-1 and time-2), but not with air.
Conclusions
Significantly, the recruitment frequency of PRS and PLESRR increases with maturation, liquid is a superior medium for evoking such swallowing reflexes, and stimulus-response relationships for these reflexes are evident. These changes in aerodigestive protective reflexive activity may indicate differences in modulation of excitatory and inhibitory pathways during longitudinal postnatal maturation.
doi:10.1038/pr.2014.147
PMCID: PMC4268006  PMID: 25279989
20.  Abnormal CD4 + T helper (Th) 1 cells and activated memory B cells are associated with type III asymptomatic mixed cryoglobulinemia in HCV infection 
Virology Journal  2015;12:100.
Background
Mixed cryoglobulinemia (MC) in hepatitis C virus (HCV) infection is associated with abnormal immune responses mediated by T cells and B cells, while the relationships of different subsets of CD4 + T helper (Th) cells, B cells and associated cytokines with type III asymptomatic MC in HCV infection are poorly understood.
Methods
Fifty-four chronic hepatitis C (CHC) patients and 23 healthy controls (HCs) were enrolled in the study. Serum cryoglobulins were detected by cryoprecipitation. The types of cryoglobulin were determined by western blot. The phenotypes and frequencies of Th cell and B cell subsets were detected by flow cytometric analysis. The cytokines IFN-γ, IL-4, IL-17, IL-21, IL-22, and TGF-β were measured by enzyme-linked immunosorbent assay.
Results
Twenty-six CHC patients were detected with type III asymptomatic MC. The frequencies of Th2, Th17, follicular helper T (Tfh cells), Th22, and tissue-like B cells were significantly higher in CHC patients compared to HCs, while these cell subsets were not significantly different between CHC patients and HCV-related MC patients. The frequencies of Th1 and activated memory B cells increased in HCV-related MC patients compared to HCs, although the difference between the two cell subsets in CHC patients and HCs was not significant. The frequency of regulatory T cells (Treg cells) was higher in CHC patients than in HCV-related MC patients and HCs. Higher expressions of serum IFN-γ, IL-17, IL-21, and IL-22 were observed in CHC patients than in HCs, but the differences were not significantly different in CHC patients and HCV-related MC patients. The frequency of Th1 cells was associated with activated memory B cells in HCV-related MC patients, and the frequency of Th1 cells and activated memory B cells was closely related to HCV RNA in HCV-related MC patients.
Conclusions
The increased frequencies of Th17 cells, Tfh cells, Th22 cells, Treg cells, cytokines IL-17, IL-21, IL-22, and tissue-like B cells, were related to HCV infection but not type III asymptomatic MC. Higher frequencies of Th1 cells and activated memory B cells were associated with type III asymptomatic MC in HCV infection.
doi:10.1186/s12985-015-0324-2
PMCID: PMC4501109  PMID: 26129991
Hepatitis C; Type III asymptomatic cryoglobulinemia; CD4+ T helper cells; Activated memory B cells
21.  Baseline Serum Albumin Is a Predictive Biomarker for Patients With Advanced Pancreatic Cancer Treated With Bevacizumab 
Cancer  2014;120(12):1780-1786.
BACKGROUND
Phase 3 studies of bevacizumab in patients with advanced pancreatic cancer (APCA) demonstrated no improvement in outcome. To the authors’ knowledge, no validated predictive biomarkers for bevacizumab exist, although emerging data suggest that subsets of patients with APCA may benefit from treatment with bevacizumab. The authors evaluated baseline serum albumin (b-alb) as a predictive biomarker in a pooled analysis from 7 prospective clinical trials of gemcitabine-based therapy with or without bevacizumab.
METHODS
Data were collected from individual databases from 7 prospective clinical trials. Patients were grouped by exposure to bevacizumab and by b-alb level (≥ 3.4 g/L or < 3.4 g/dL). Overall survival (OS), time to disease progression (TTP), overall response rate, and disease control rate (overall response rate plus stable disease lasting ≥ 16 weeks) were compared between groups. Univariate and multivariable analyses of prognostic factors were performed.
RESULTS
A total of 264 patients were included. The median age was 59 years (range, 31 years-85 years) and all patients had stage IV disease per TNM staging. Normal b-alb was associated with significantly improved median OS (10.2 months vs 4.1 months; P =.0001), median TTP (6.2 months vs 3.7 months; P = 0.0488), and disease control rate (71% vs 46%; P =.007) for patients receiving bevacizumab, but not for those treated without bevacizumab. Multivariable analysis revealed a significant influence of normal b-alb on OS (P =.0008) and TTP (P =.033).
CONCLUSIONS
Patients with APCA with normal b-alb derive benefit from treatment with bevacizumab. Future prospective investigations of bevacizumab in patients with APCA should consider selecting patients with normal b-alb to maximize potential benefit.
doi:10.1002/cncr.28648
PMCID: PMC4265390  PMID: 24633933
pancreatic cancer; albumin; bevacizumab; predictive biomarker
22.  A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum-based therapy 
Background
The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. Thus, we performed a clinical trial examining the efficacy of the combination of these agents in the treatment of GE and E cancer.
Methods
A Fleming phase II design with a single stage of 32 patients was planned. Pralatrexate 120 mg/m2 and docetaxel 35 mg/m2 were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS).
Results
The study was halted prematurely due to loss of funding after the accrual of six patients. Two patients had stable disease (SD) and four patients had disease progression per RECIST. When applying PERCIST criteria in four evaluable patients, two had a partial response (PR) and two had SD. Median PFS was 1.9 months (95% CI, 0.8-7.2) and median OS was 5.5 (0.8-11.7) months.
Conclusions
Pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity. PERCIST may prove to better assess the meaningfulness of anatomic SD.
doi:10.3978/j.issn.2078-6891.2015.011
PMCID: PMC4397239  PMID: 26029462
Pralatrexate; docetaxel; gastrointestinal neoplasms; esophageal (E) cancer
23.  MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis 
Oncotarget  2015;6(15):13658-13670.
MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.
PMCID: PMC4537040  PMID: 25909223
hepatocellular carcinoma; miR-200 family; cytoskeletal reorganization; Rho/ROCK signaling pathway; cancer metastasis
24.  PAPST, a User Friendly and Powerful Java Platform for ChIP-Seq Peak Co-Localization Analysis and Beyond 
PLoS ONE  2015;10(5):e0127285.
Comparative co-localization analysis of transcription factors (TFs) and epigenetic marks (EMs) in specific biological contexts is one of the most critical areas of ChIP-Seq data analysis beyond peak calling. Yet there is a significant lack of user-friendly and powerful tools geared towards co-localization analysis based exploratory research. Most tools currently used for co-localization analysis are command line only and require extensive installation procedures and Linux expertise. Online tools partially address the usability issues of command line tools, but slow response times and few customization features make them unsuitable for rapid data-driven interactive exploratory research. We have developed PAPST: Peak Assignment and Profile Search Tool, a user-friendly yet powerful platform with a unique design, which integrates both gene-centric and peak-centric co-localization analysis into a single package. Most of PAPST’s functions can be completed in less than five seconds, allowing quick cycles of data-driven hypothesis generation and testing. With PAPST, a researcher with or without computational expertise can perform sophisticated co-localization pattern analysis of multiple TFs and EMs, either against all known genes or a set of genomic regions obtained from public repositories or prior analysis. PAPST is a versatile, efficient, and customizable tool for genome-wide data-driven exploratory research. Creatively used, PAPST can be quickly applied to any genomic data analysis that involves a comparison of two or more sets of genomic coordinate intervals, making it a powerful tool for a wide range of exploratory genomic research. We first present PAPST’s general purpose features then apply it to several public ChIP-Seq data sets to demonstrate its rapid execution and potential for cutting-edge research with a case study in enhancer analysis. To our knowledge, PAPST is the first software of its kind to provide efficient and sophisticated post peak-calling ChIP-Seq data analysis as an easy-to-use interactive application. PAPST is available at https://github.com/paulbible/papst and is a public domain work.
doi:10.1371/journal.pone.0127285
PMCID: PMC4430287  PMID: 25970601
25.  Is Helicobacter pylori infection associated with glycemic control in diabetics? 
AIM: To investigate whether Helicobacter pylori (H. pylori) infection is associated with glycemic control and whether hyperglycemia is modified by eradication therapy.
METHODS: The databases of PubMed, Cochrane Library, Chinese BioMedicine Web Base and Chinese Science and Technology Journals were searched from inception to June 2014. Studies examining the association between H. pylori infection and glycemic control and⁄or the effect of eradication treatment on glycemic control in diabetic humans were eligible for inclusion. Meta-analyses were conducted using the Review Manager software version 5.2. The outcome measures are presented as weighed mean differences (WMDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed by the Cochran Q test and the I2 statistic.
RESULTS: A total of 21 relevant publications were identified. A meta-analysis of 11 studies with 513 patients with diabetes mellitus (DM) showed significantly lower glycosylated hemoglobin (HbA1c) levels in the H. pylori-negative than H. pylori-positive DM participants (WMD = 0.43, 95%CI: 0.07-0.79; P = 0.02). In children and adolescents with type 1 DM (T1DM), there was a positive association between H. pylori infection and HbA1c level (WMD = 0.35, 95%CI: 0.05-0.64; P = 0.02), but there was no difference in those with type 2 DM (T2DM, WMD = 0.51, 95%CI: -0.63-1.65; P = 0.38). A meta-analysis of six studies with 325 T2DM participants showed a significant difference in the fasting plasma glucose levels between H. pylori-positive and H. pylori-negative participants (WMD = 1.20, 95%CI: 0.17-2.23; P = 0.02). Eradication of H. pylori did not improve glycemic control in the T2DM participants in a three-month follow-up period (HbA1c decrease: WMD = -0.03, 95%CI = -0.14-0.08; P = 0.57; fasting plasma glucose decrease: WMD = -0.06, 95%CI: -0.36-0.23; P = 0.68). Glycemic control was significantly better in T1DM participants who were not reinfected than in those who were reinfected (HbA1c: WMD = 0.72, 95%CI: 0.32-1.13: P = 0.00).
CONCLUSION: H. pylori infection is associated with poorer glycemic control in T1DM patients, but eradication may not improve glycemic control in DM in a short-term follow-up period.
doi:10.3748/wjg.v21.i17.5407
PMCID: PMC4419082  PMID: 25954115
Diabetes mellitus; Eradication; Glycemic control; Helicobacter pylori; Meta-analysis; Reinfection

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