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1.  Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib 
Scientific Reports  2016;6:39598.
As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes. On the basis of the distinctive results, lapatinib and sunitinib were selected for further tumor-inhibition investigation and determination of the underlying mechanism. Interestingly, we found lapatinib to work better with SZU-101, enhancing tumor clearance in vivo, without affecting the TLR7-NF-κB pathway activated by the TLR7 agonist in mouse spleen lymphocytes and bone marrow dendritic cells (BMDCs).
doi:10.1038/srep39598
PMCID: PMC5175151  PMID: 28000738
2.  Discovering Genome-Wide Tag SNPs Based on the Mutual Information of the Variants 
PLoS ONE  2016;11(12):e0167994.
Exploring linkage disequilibrium (LD) patterns among the single nucleotide polymorphism (SNP) sites can improve the accuracy and cost-effectiveness of genomic association studies, whereby representative (tag) SNPs are identified to sufficiently represent the genomic diversity in populations. There has been considerable amount of effort in developing efficient algorithms to select tag SNPs from the growing large-scale data sets. Methods using the classical pairwise-LD and multi-locus LD measures have been proposed that aim to reduce the computational complexity and to increase the accuracy, respectively. The present work solves the tag SNP selection problem by efficiently balancing the computational complexity and accuracy, and improves the coverage in genomic diversity in a cost-effective manner. The employed algorithm makes use of mutual information to explore the multi-locus association between SNPs and can handle different data types and conditions. Experiments with benchmark HapMap data sets show comparable or better performance against the state-of-the-art algorithms. In particular, as a novel application, the genome-wide SNP tagging is performed in the 1000 Genomes Project data sets, and produced a well-annotated database of tagging variants that capture the common genotype diversity in 2,504 samples from 26 human populations. Compared to conventional methods, the algorithm requires as input only the genotype (or haplotype) sequences, can scale up to genome-wide analyses, and produces accurate solutions with more information-rich output, providing an improved platform for researchers towards the subsequent association studies.
doi:10.1371/journal.pone.0167994
PMCID: PMC5161470  PMID: 27992465
3.  Novel antimicrobial peptide–modified azithromycin-loaded liposomes against methicillin-resistant Staphylococcus aureus 
Infections caused by multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), have become a public threat; therefore, development of new antimicrobial drugs or strategies is urgently required. In this study, a new antibacterial peptide DP7-C (Chol-suc-VQWRIRVAVIRK-NH2) and DP7-C-modified azithromycin (AZT)-loaded liposomes (LPs) are developed for the treatment of MRSA infection, and it was found that DP7-C inserted into the LP lipid bilayer not only functioned as a carrier to encapsulate the antibiotic AZT but also synergized the antibacterial effect of the encapsulated AZT. In vitro assays showed that DP7-C-modified LPs possessed sustained drug release profile and immune regulatory effect and did not show obvious cytotoxicity in mammal cells, but they did not possess direct antibacterial activity in vitro. In vivo studies revealed that DP7-C-modified LPs did not exhibit obvious side effects or toxicity in mice but were able to significantly reduce the bacterial counts in an MRSA-infectious mouse model and possessed high antibacterial activity. In particular, DP7-C-modified AZT-loaded LPs showed more positive therapeutic effects than either DP7-C-modified blank LPs or nonmodified AZT-loaded LPs treatment alone. Molecular mechanism studies demonstrated that DP7-C formulations effectively upregulated the production of anti-inflammatory cytokines and chemokines without inducing harmful immune response, suggesting that DP7-C was synergistic with AZT against the bacterial infection by activating the innate immune response. Most importantly, although DP7-C activated the innate immune response, it did not possess direct antibacterial activity in vitro, indicating that DP7-C did not possess the potential to induce bacteria resistance. The findings indicate that DP7-C-modified AZT-loaded LPs developed in this study have a great potential required for the clinical treatment of MRSA infections.
doi:10.2147/IJN.S107107
PMCID: PMC5167457  PMID: 28008253
DP7-C; azithromycin; antimicrobial resistance; MRSA infections; immune-regulation
4.  Fast and Robust Reconstruction for Fluorescence Molecular Tomography via L1-2 Regularization 
BioMed Research International  2016;2016:5065217.
Sparse reconstruction inspired by compressed sensing has attracted considerable attention in fluorescence molecular tomography (FMT). However, the columns of system matrix used for FMT reconstruction tend to be highly coherent, which means L1 minimization may not produce the sparsest solution. In this paper, we propose a novel reconstruction method by minimization of the difference of L1 and L2 norms. To solve the nonconvex L1-2 minimization problem, an iterative method based on the difference of convex algorithm (DCA) is presented. In each DCA iteration, the update of solution involves an L1 minimization subproblem, which is solved by the alternating direction method of multipliers with an adaptive penalty. We investigated the performance of the proposed method with both simulated data and in vivo experimental data. The results demonstrate that the DCA for L1-2 minimization outperforms the representative algorithms for L1, L2, L1/2, and L0 when the system matrix is highly coherent.
doi:10.1155/2016/5065217
PMCID: PMC5168556  PMID: 28050563
5.  Successful selective reduction of a heterotopic cesarean scar pregnancy in the second trimester: a case report and review of the literature 
Background
Heterotopic cesarean scar pregnancy is a cesarean scar pregnancy combined with an intrauterine pregnancy that predisposes a woman to life-threatening complications such as uterine rupture and massive bleeding. Preservation of the intrauterine pregnancy in heterotopic cesarean scar pregnancy is a great challenge.
Case presentation
We report a case of a 33-year-old woman with heterotopic cesarean scar pregnancy after IVF-embryo transfer (ET). Expectant management was carried out with early diagnosis of heterotopic cesarean scar pregnancy (HCSP), and selective fetal reduction of cesarean scar pregnancy (CSP) was performed by ultrasound-guided intrathoracic injection of potassium chloride (KCl) at 16 + 4 weeks of gestation due to aggravation of CSP. Preservation of the intrauterine pregnancy was successful and a healthy baby was delivered by cesarean section at 37 + 6 weeks of gestation.
Conclusions
Heterotopic cesarean scar pregnancy is an extremely rare form of heterotopic pregnancy. Patients should be appropriately counseled regarding the different treatment options available. An ultrasound-guided injection of potassium chloride may constitute a safe, minimally invasive and reliable way to terminate the heterotopic gestation and preserve the intrauterine pregnancy. Intensive management should be performed during the ongoing pregnancy and cesarean section.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-016-1171-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-016-1171-x
PMCID: PMC5126867  PMID: 27894281
Heterotopic cesarean scar pregnancy; Potassium chloride; Selective fetal reduction; Expectant management
6.  Pregnancy outcome in women with Eisenmenger’s syndrome: a case series from west China 
Background
Eisenmenger’s syndrome (ES) consists of pulmonary hypertension with a reversed or bidirectional shunt at the atrioventricular, or aortopulmonary level.
The cardiovascular changes that occur during the pregnancy contribute to the high maternal morbidity and mortality in patients with ES. This study is to assess maternal and fetal outcomes in patients with ES.
Methods
This study is a retrospective analysis of 11 pregnancies in women with ES who delivered at a tertiary care center in west China between 2010 and 2014. Cases were divided into group I (maternal survival) and group II (maternal death). Clinical data were noted and analyzed.
Results
All ES patients presented with severe pulmonary arterial hypertension (PAH). Four maternal deaths were recorded (maternal mortality of 36%). Only one pregnancy continued to term. Ventricular septal defect diameter in group II was larger than that in group I (2.93 ± 0.76 cm vs. 1.90 ± 0.54 cm, p < 0.05). Arterial oxygen saturation and pre-delivery arterial oxygen tension during oxygen inhalation were significantly lower in group II (p < 0.05). Pulmonary arterial blood pressure (PABP) in both groups were high while ejection fractions (EF) were significantly lower in group II (p < 0.05). The incidence of pre-delivery heart failure in group II was substantially higher than in survivors (100 vs.14.3%, p < 0.05). Fetal complications were exceptionally high: preterm delivery (88%), small for gestational age (83%), fetal mortality (27%) and neonatal mortality (25%).
Conclusions
In west China,the perinatal outcome of pregnant women with ES is poor, especially when complicated with high pulmonary arterial hypertension (PAH). Pregnancy remains strongly contraindicated in ES. Effective contraception is essential, and the option of terminating pregnancy in the first trimester should be presented to pregnant women with ES.
doi:10.1186/s12884-016-1153-z
PMCID: PMC5112756  PMID: 27852228
Pregnancy; Eisenmenger’s syndrome (ES); Pulmonary arterial hypertension (PAH); Maternal outcome; Fetal outcome
7.  MERTK Inhibition Induces Polyploidy and Promotes Cell Death and Cellular Senescence in Glioblastoma Multiforme 
PLoS ONE  2016;11(10):e0165107.
Background
MER receptor tyrosine kinase (MERTK) is expressed in a variety of malignancies, including glioblastoma multiforme (GBM). Our previous work demonstrated that inhibition of MERTK using RNA interference induced cell death and chemosensitivity in GBM cells, implicating MERTK as a potential therapeutic target. Here we investigate whether a novel MERTK-selective small molecule tyrosine kinase inhibitor, UNC2025, has similar anti-tumor effects in GBM cell lines.
Methods
Correlations between expression of GAS6, a MERTK ligand, and prognosis were determined using data from the TCGA database. GBM cell lines (A172, SF188, U251) were treated in vitro with increasing doses of UNC2025 (50-400nM). Cell count and viability were determined by trypan blue exclusion. Cell cycle profiles and induction of apoptosis were assessed by flow cytometric analysis after BrdU or Po-Pro-1/propidium iodide staining, respectively. Polyploidy was detected by propidium iodide staining and metaphase spread. Cellular senescence was determined by β-galactosidase staining and senescence-associated secretory cytokine analysis.
Results
Decreased overall survival significantly correlated with high levels of GAS6 expression in GBM, highlighting the importance of TAM kinase signaling in GBM tumorigenesis and/or therapy resistance and providing strong rationale for targeting these pathways in the clinic. All three GBM cell lines exhibited dose dependent reductions in cell number and colony formation (>90% at 200nM) after treatment with UNC2025. Cell cycle analysis demonstrated accumulation of cells in the G2/M phase and development of polyploidy. After extended exposure, 60–80% of cells underwent apoptosis. The majority of surviving cells (65–95%) were senescent and did not recover after drug removal. Thus, UNC2025 mediates anti-tumor activity in GBM by multiple mechanisms.
Conclusions
The findings described here provide further evidence of oncogenic roles for MERTK in GBM, demonstrate the importance of kinase activity for MERTK tumorigenicity and validate UNC2025, a novel MERTK inhibitor, as a potential therapeutic agent for treatment of GBM.
doi:10.1371/journal.pone.0165107
PMCID: PMC5081168  PMID: 27783662
8.  Changes in the Expression of miR-34a and its Target Genes Following Spinal Cord Injury In Rats 
Background
Results from DNA microarray experiments have shown that the expression of miR-34s undergoes significant changes following spinal cord injury (SCI). The present study was designed to detect changes in the expression of miR-34s and its target genes during the acute and sub-acute stages of SCI.
Material/Methods
Luxol fast blue (LFB) staining for myelin was used to observe the differences in the general morphology of the spinal cord after SCI in a contusion model in rats. qPCR was carried out to determine the expression variation of miR-34s and its target genes during the acute and sub-acute stages of SCI. The mimic technique was used to further confirm the regulatory effect of miR-34a on the potential target genes.
Results
The expression level of miR-34a decreased immediately after SCI and persisted for 21 days after SCI. The expression level of miR-34c began decreasing at day 1 after SCI and persisted until day 14. The expression level of miR-34b did not undergo significant change after SCI. The results of double immunofluorescence and in-situ hybridization suggested that miR-34a was highly expressed in spinal cord neurons. Based on our bioinformatics analysis, we postulated that miR-34a might participate in post-SCI cell apoptosis by regulating the target gene Notch1, and likely participated in the inflammatory response and glial scar formation by regulating the candidate genes Csf1r and PDGFRα, respectively. The expression levels of the candidate genes Csf1r and PDGFRα were consistent with Notch1 after SCI. The mimic technique further confirmed the regulatory effect of miR-34a on the aforementioned target genes.
Conclusions
We postulate that miR-34a and miR-34c might participate in multiple aspects of cytobiological activities following SCI. MiR-34a in particular may participate in cell apoptosis, inflammatory response, and glial scar formation by regulating the target gene Notch1 and candidate target genes Csf1r and PDGFRα respectively.
doi:10.12659/MSM.900893
PMCID: PMC5083044  PMID: 27780189
MicroRNAs; Receptor, Macrophage Colony-Stimulating Factor; Receptor, Notch1; Receptor, Platelet-Derived Growth Factor alpha; Spinal Cord Injuries
9.  Reconstruction for Limited-Projection Fluorescence Molecular Tomography Based on a Double-Mesh Strategy 
BioMed Research International  2016;2016:5682851.
Limited-projection fluorescence molecular tomography (FMT) has short data acquisition time that allows fast resolving of the three-dimensional visualization of fluorophore within small animal in vivo. However, limited-projection FMT reconstruction suffers from severe ill-posedness because only limited projections are used for reconstruction. To alleviate the ill-posedness, a feasible region extraction strategy based on a double mesh is presented for limited-projection FMT. First, an initial result is rapidly recovered using a coarse discretization mesh. Then, the reconstructed fluorophore area in the initial result is selected as a feasible region to guide the reconstruction using a fine discretization mesh. Simulation experiments on a digital mouse and small animal experiment in vivo are performed to validate the proposed strategy. It demonstrates that the presented strategy provides a good distribution of fluorophore with limited projections of fluorescence measurements. Hence, it is suitable for reconstruction of limited-projection FMT.
doi:10.1155/2016/5682851
PMCID: PMC5086542  PMID: 27830148
10.  Lipiodol retention pattern assessed by cone beam computed tomography during conventional transarterial chemoembolization of hepatocellular carcinoma: accuracy and correlation with response 
Cancer Imaging  2016;16:32.
Background
To investigate accuracy of intraprocedural cone beam computed tomography (CBCT) compared to fluoroscopy for detection of lipiodol retention pattern during conventional transarterial chemoembolization (cTACE) of hepatocellular carcinoma (HCC) and its correlation with short-term response.
Methods
Between September 2013 and July 2014, 29 patients with HCC underwent chemoembolization of 51 tumors (mean diameter 28.1 mm, range 10.0–136.3 mm). Lipiodol retention pattern was assessed by CBCT at the endpoint of cTACE compared by fluoroscopy. Depending on the pattern of tumor covered by lipiodol three classes were defined: complete (more than 90 %, no peripheral defects), moderate (50–90 %, some with or without peripheral defects), and poor (less than 50 %). Tumor response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on follow-up contrast enhanced (CE) computed tomography (CT) or magnetic resonance imaging (MRI) obtained 4–6 weeks post-cTACE. Correlations between lipiodol retention patterns on CBCT and fluoroscopy as well as tumor response were assessed using multivariate logistic regression.
Results
Of 51 hepatic tumors, 40 (78.4 %) had complete response (CR); 8 (15.7 %) had partial response (PR); 1 (2.0 %) had stable disease (SD); and 2 (3.9 %) had progressive disease (PD). The degree of lipiodol retention scored excellent, moderate, and poor, in fluoroscopic images vs CBCT images were 23 (45.1 %) vs 39 (76.5 %), 19 (37.3 %) vs 11 (21.6 %), and 9 (17.6 %) vs 1 (2.0 %), respectively. Lipiodol retention assessment with CBCT (Az = 0.75) is more accurate than fluoroscopy (Az = 0.54) in predicting target tumor response. Other than lipiodol retention pattern assessed with CBCT (p = 0.01), tumor size (p = 0.04) is an independent predictors of CR.
Conclusion
CBCT is more accurate than fluoroscopy in classification of lipiodol retention pattern in HCC tumors at the time of cTACE. CBCT could be used as a reliable intra precedural monitoring modality of cTACE.
doi:10.1186/s40644-016-0090-4
PMCID: PMC5048686  PMID: 27716376
Cone beam computed tomography; Fluoroscopy; Transarterial chemoembolization; Hepatocellular carcinoma; Liver
11.  Association of SLCO2B1 Genotypes With Time to Progression and Overall Survival in Patients Receiving Androgen-Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2015;34(4):352-359.
Purpose
To validate the association of three previously demonstrated SLCO2B1 germline variants with time to progression (TTP) in patients receiving androgen-deprivation therapy (ADT), and to evaluate if the SLCO2B1 genetic variants impacted overall survival (OS) for prostate cancer (PC).
Patients and Methods
Three single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in an independent validation cohort of 616 patients with PC who were treated with ADT at the Dana-Farber Cancer Institute from 1996 to 2013. Multivariable Cox proportional hazards regression adjusting for known prognostic factors estimated the association of these genetic variants with TTP and OS in patients receiving ADT. The expression of SLCO2B1 was examined in prostatectomy samples, and the impact of SLCO2B1 expression level on DHEAS (dehydroepiandrosterone sulfate) uptake was evaluated in cell lines.
Results
The association between exonic SNP rs12422149 and TTP in patients treated with ADT was confirmed in univariable (P = .019) and multivariable analyses (adjusted hazard ratio, 1.31; 95% CI, 1.00 to 1.72 for GG v AA/AG; P = .049). Because OS had not been previously evaluated, we examined the association in the combined initial and validation cohorts (N = 1,094). The intronic SNP rs1077858 was associated with OS in both univariable (P = .009; Bonferroni’s method adjusted P = .027) and multivariable analyses (adjusted hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for GG v AA/AG; P = .012). SLCO2B1 expression in normal prostate tissue and in 22RV1 cells carrying the major allele of SNP rs1077858 was significantly lower than in cells carrying the risk allele. We show in vitro that SLCO2B1 expression levels correlated with DHEAS uptake by PC cells.
Conclusion
The association of SNP rs1077858 with OS may be a result of differential SLCO2B1 expression and the consequent increased uptake of DHEAS and subsequent resistance to ADT, which, in turn, may contribute to decreased OS.
doi:10.1200/JCO.2015.62.5988
PMCID: PMC4872031  PMID: 26668348
12.  17β-estradiol ameliorates oxygen-induced retinopathy in the early hyperoxic phase 
Retinopathy of prematurity (ROP) is a major and leading cause of blindness in premature infants. It has been realized that early treatment for ROP is important. However, all the early treatments of ROP are focusing on peripheral retinal ablation which does not surmount the limit of extinguishing retinal neovascularization and protecting the retinas of children with ROP from the injury of ablation. In this study, we investigated the morphological changes of retina and oxidative stress alterations in the early phase of oxygen-induced retinopathy (OIR) and tested the effects of 17β-estradiol (17β-E2) , a nonselective estrogen receptor (ER) agonist, on early phase OIR development. We found that large central capillary-free areas were induced in the retinas of pups exposed to hyperoxia on postnatal day 9 (P9) , whereas vascularization was almost complete in the retinas of pups exposed to normoxia at the same age. The concentrations of malondiadehyde (MDA) , an end-product of oxidative stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major enzyme producing free radicals, as well as the activity of NADPH oxidase were significantly elevated in the retinas of pups exposed to hyperoxia on P9 and postnatal day 13 (P13) compared to those in age matched pups exposed to normoxia. Treatment with 17β-E2 decreased not only the percentage of the central capillary-free area to total retina area but also the concentrations of MDA and NADPH oxidase as well as the activity of NADPH oxidase in a dose-dependent manner in pups exposed to hyperoxia on p9 and P13. The concentration of VEGF was significantly decreased on P9 but increased on P14 in the retinas of pups exposed to hyperoxia, whereas it was significantly elevated on P9 but decreased on P14 in the retinas of pups treated with 17β-E2. The effect of 17β-E2 could be reversed by the co-treatment with ICI182780, a high affinity estrogen receptor antagonist, which suggested that 17β-E2 might exert its effect on early hyperoxic phase of OIR through estrogen receptor. Our results suggest that treatment with antioxidant drugs at early hyperoxic phase of ROP even before the appearance of retinal neovascularization may be more effective than their application to ROP at late phase, which may abolish the deleterious factors that contribute to retinal neovascularization and promote retinal blood vessels to develop healthily.
doi:10.1016/j.bbrc.2015.01.052
PMCID: PMC5040126  PMID: 25619134
oxygen-induced retinopathy; oxidative stress; 17β-estradiol; receptor; NADPH oxidase
13.  Germline Variation in Superoxide Dismutase-2 (SOD2) and Survival Outcomes after Radiation Therapy for Prostate Cancer: Results from a Test and Validation Set Analysis 
Clinical genitourinary cancer  2015;13(4):370-377.e1.
Background
Genetic variants in antioxidant pathways may decrease the efficacy of radiation therapy (RT) by suppressing the generation of reactive oxygen species (ROS). We studied the association between single nucleotide polymorphisms (SNPs) in the antioxidant gene superoxide dismutase-2 (SOD2) and cancer-specific outcomes after RT.
Methods
Among 816 prostate cancer patients who received radiation as primary therapy from the Physicians’ Health Study and the Health Professionals Follow-up Study, we evaluated the association of 7 tagging SNPs in SOD2 with lethal prostate cancer (death from prostate cancer or distant metastasis among living patients). We sought to validate findings in a separate cohort of 612 prostate cancer patients treated with RT with a higher proportion of intermediate and high-risk Gleason scores at the Dana-Farber Cancer Institute. Genetic effects were analyzed using a co-dominant model, using the genotype homozygous for the major allele as baseline.
Results
Among patients who underwent RT in the test cohort, there was a significant association between three of the seven SOD2 SNPs and lethal prostate cancer: rs6917589 (overall p-value =0.006), rs2758331 (p=0.04) and the functional valine to alanine polymorphism in rs4880 (p=0.04). These SNPs were not associated with outcome among men who had undergone prostatectomy. The associations were not replicated in the validation cohort.
Conclusion
Germline genetic variation in the SOD2 gene may be a predictive biomarker of response to radiation therapy for prostate cancer but is not consistently associated with outcome after radiation therapy across prostate cancer cohorts with different clinical characteristics.
doi:10.1016/j.clgc.2014.12.018
PMCID: PMC5038132  PMID: 25662905
antioxidant; radiation therapy; superoxide dismutase; SOD2; free radicals; reactive oxygen species; prostate cancer outcomes
14.  Effect of silencing SATB1 on proliferation, invasion and apoptosis of A549 human lung adenocarcinoma cells 
Oncology Letters  2016;12(5):3818-3824.
The present study aimed to explore the clinical characteristics of special adenine-thymine-rich sequence-binding protein 1 (SATB1) in lung adenocarcinoma and its role in the proliferation, invasion, migration and apoptosis of the lung adenocarcinoma cell line A549. The expression of SATB1 was first studied in tumor tissues of lung adenocarcinoma and adjacent non-tumor tissues. The siRNA green fluorescent protein expression vector of SATB1 was constructed and transfected into the lung adenocarcinoma cell line A549, then a fluorescence microscope was used to study the transfection efficiency. Western blot analysis was adopted to measure the silencing efficiency. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell and scratch assays were used to study cell proliferation, invasion and migration activity, and the apoptosis rate was tested by flow cytometry. SATB1 expression was low in the adjacent non-tumor tissues but high in lung adenocarcinoma tissues, and it was reversely proportional to the differentiation degree. Following transfection with SATB1-siRNA, the expression of SATB1 in A549 cells was blocked (P<0.01). In addition, the proliferation, invasion and migration abilities of cells decreased significantly while the apoptosis rate increased significantly (P<0.01). In conclusion SATB1 is closely associated with the pathogenesis and development of lung adenocarcinoma.
doi:10.3892/ol.2016.5179
PMCID: PMC5104178  PMID: 27895736
lung cancer; siRNA; special adenine-thymine-rich sequence-binding protein 1
15.  Pirfenidone in patients with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis 
Scientific Reports  2016;6:33226.
To evaluate the efficacy of pirfenidone in patients with rapidly progressive interstitial lung disease (RPILD) related to clinically amyopathic dermatomyositis (CADM), we conducted an open-label, prospective study with matched retrospective controls. Thirty patients diagnosed with CADM-RPILD with a disease duration <6 months at Renji Hospital South Campus from June 2014 to November 2015 were prospectively enrolled and treated with pirfenidone at a target dose of 1800 mg/d in addition to conventional treatment, such as a glucocorticoid and/or other immunosuppressants. Matched patients without pirfenidone treatment (n = 27) were retrospectively selected as controls between October 2012 and September 2015. We found that the pirfenidone add-on group displayed a trend of lower mortality compared with the control group (36.7% vs 51.9%, p = 0.2226). Furthermore, the subgroup analysis indicated that the pirfenidone add-on had no impact on the survival of acute ILD patients (disease duration <3 months) (50% vs 50%, p = 0.3862); while for subacute ILD patients (disease duration 3–6 months), the pirfenidone add-on (n = 10) had a significantly higher survival rate compared with the control subgroup (n = 9) (90% vs 44.4%, p = 0.0450). Our data indicated that the pirfenidone add-on may improve the prognosis of patients with subacute ILD related to CADM.
doi:10.1038/srep33226
PMCID: PMC5018967  PMID: 27615411
16.  Small molecule inhibition of MERTK is efficacious in non-small cell lung cancer models independent of driver oncogene status 
Molecular cancer therapeutics  2015;14(9):2014-2022.
Treatment of non-small cell lung cancer (NSCLC) has been transformed by targeted therapies directed against molecular aberrations specifically activated within an individual patient’s tumor. However, such therapies are currently only available against a small number of such aberrations, and new targets and therapeutics are needed. Our laboratory has previously identified the MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple cancer types, including NSCLC. We have recently developed UNC2025 – the first-in-class small molecule inhibitor targeting MERTK with pharmacokinetic properties sufficient for clinical translation. Here we utilize this compound to further validate the important emerging biologic functions of MERTK in lung cancer pathogenesis, to establish that MERTK can be effectively targeted by a clinically translatable agent, and to demonstrate that inhibition of MERTK is a valid treatment strategy in a wide variety of non-small cell lung cancer cell lines independent of their driver oncogene status, including in lines with an EGFR mutation, a KRAS/NRAS mutation, an RTK fusion, or another or unknown driver oncogene. Biochemically, we report the selectivity of UNC2025 for MERTK, and its inhibition of oncogenic downstream signaling. Functionally, we demonstrate that UNC2025 induces apoptosis of MERTK-dependent NSCLC cell lines, while decreasing colony formation in vitro and tumor xenograft growth in vivo in murine models. These findings provide further evidence for the importance of MERTK in NSCLC, and demonstrate that MERTK inhibition by UNC2025 is a feasible, clinically relevant treatment strategy in a wide variety of NSCLC sub-types, which warrants further investigation in clinical trials.
doi:10.1158/1535-7163.MCT-15-0116
PMCID: PMC4704683  PMID: 26162689
MERTK; Non-Small Cell Lung Cancer; Small Molecule Inhibitor; Targeted Therapy; Receptor Tyrosine Kinase
17.  Synthesis of jet fuel range branched cycloalkanes with mesityl oxide and 2-methylfuran from lignocellulose 
Scientific Reports  2016;6:32379.
Jet fuel range branched cycloalkanes with high density (0.82 g mL−1) and low freezing point (217–219 K) was first prepared by the solvent-free intramolecular aldol condensation of the trione from the hydrolysis of the alkylation product of mesityl oxide and 2-methylfuran (or the one-pot reaction of mesityl oxide, 2-methylfuran and water), followed by hydrodeoxygenation (HDO).
doi:10.1038/srep32379
PMCID: PMC5007666  PMID: 27582417
18.  Overview of the interactive task in BioCreative V 
Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user participation were offered to broaden curator involvement and obtain more feedback on usability aspects. The full level participation involved training on the system, curation of a set of documents with and without TM assistance, tracking of time-on-task, and completion of a user survey. The partial level participation was designed to focus on usability aspects of the interface and not the performance per se. In this case, biocurators navigated the system by performing pre-designed tasks and then were asked whether they were able to achieve the task and the level of difficulty in completing the task. In this manuscript, we describe the development of the interactive task, from planning to execution and discuss major findings for the systems tested.
Database URL: http://www.biocreative.org
doi:10.1093/database/baw119
PMCID: PMC5009325  PMID: 27589961
19.  Three-dimensional co-culture of mesenchymal stromal cells and differentiated osteoblasts on human bio-derived bone scaffolds supports active multi-lineage hematopoiesis in vitro: Functional implication of the biomimetic HSC niche 
Recent studies have indicated that the hematopoietic stem/progenitor cell (HSPC) niche, consisting of two major crucial components, namely osteoblasts (OBs) and mesenchymal stromal cells (MSCs), is responsible for the fate of HSPCs. Thus, closely mimicking the HSPC niche ex vivo may be an efficient strategy with which to develop new culture strategies to specifically regulate the balance between HSPC self-renewal and proliferation. The aim of this study was to establish a novel HSPC three-dimensional culture system by co-culturing bone marrow-derived MSCs and OBs differentiated from MSCs without any cytokines as feeder cells and applying bio-derived bone from human femoral metaphyseal portion as the scaffold. Scanning electron microscopy revealed the excellent biocompatibility of bio-derived bone with bone marrow-derived MSCs and OBs differentiated from MSCs. Western blot analysis revealed that many cytokines, which play key roles in HSPC regulation, were comprehensively secreted, while ELISA revealed that extracellular matrix molecules were also highly expressed. Hoechst 33342/propidium iodide fluorescence staining proved that our system could be used to supply a long-term culture of HSPCs. Flow cytometric analysis and qPCR of p21 expression demonstrated that our system significantly promoted the self-renewal and ex vivo expansion of HSPCs. Colony-forming unit (CFU) and long-term culture-initiating cell (LTC-IC) assays confirmed that our system has the ability for both the expansion of CD34+ hematopoietic stem cells (HPCs) and the maintenance of a primitive cell subpopulation of HSCs. The severe-combined immunodeficient mouse repopulating cell assay revealed the promoting effects of our system on the expansion of long-term primitive transplantable HSCs. In conclusion, our system may be a more comprehensive and balanced system which not only promotes the self-renewal and ex vivo expansion of HSPCs, but also maintains primitive HPCs with superior phenotypic and functional attributes.
doi:10.3892/ijmm.2016.2712
PMCID: PMC5029969  PMID: 27571775
osteoblasts; mesenchymal stromal cells; hematopoietic stem/progenitor cell niche; three-dimensional culture system
20.  The Diagnosis of Iliac Bone Destruction in Children: 22 Cases from Two Centres 
BioMed Research International  2016;2016:2131859.
Iliac bone destruction in children is uncommon and presents various imaging features. Correct diagnosis based on clinical and imaging features is difficult. This research aimed to retrospectively explore the clinical features, imaging, and histopathological diagnosis of children with iliac bone destruction. A total of 22 children with iliac bone destruction were enrolled in this retrospective analysis from two children's hospitals during July 2007 to April 2015. Clinical features, imaging, and histopathological findings were analysed. The mode of iliac bone destruction, lesion structure, and the relationship between the range of soft tissue mass and cortical destruction were determined based on imaging data. The data were analysed using descriptive methods. Of the iliac bone destruction cases, eight cases were neuroblastoma iliac bone metastasis, seven cases were bone eosinophilic granuloma, two cases were Ewing's sarcoma, two cases were osteomyelitis, one case was bone cyst, one case was bone fibrous dysplasia, and one case was non-Hodgkin's lymphoma. Iliac bone destruction varies widely in children. Metastatic neuroblastoma and eosinophilic granuloma are the most commonly involved childhood tumours.
doi:10.1155/2016/2131859
PMCID: PMC4992755  PMID: 27579306
21.  Reprogramming A375 cells to induced-resembled neuronal cells by structured overexpression of specific transcription genes 
Molecular Medicine Reports  2016;14(4):3134-3144.
Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete-scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain-derived neurotrophic factor (h-BDNF). irNCs induced from A375 cells express multiple neuronal markers and fire action potentials, exhibiting properties similar to those of motor neurons. The reprogramming procedure comprised reverse transcription-polymerase chain reaction and immunofluorescence staining; furthermore, electrophysiological profiling demonstrated the characteristics of the induced-resembled neurons. The present study obtained a novel type of human irNC from human melanoma, which secreted BDNF continuously, providing a model for neuron-like cells. Thus, irNCs offer promise in investigating various neural diseases by using neural-like cells derived directly from the patient of interest.
doi:10.3892/mmr.2016.5598
PMCID: PMC5042733  PMID: 27510459
genetic lineage conversion; A375; induced-resembled neuronal cells; human brain-derived neurotrophic factor
22.  Genome-wide transcriptomic analysis uncovers the molecular basis underlying early flowering and apetalous characteristic in Brassica napus L 
Scientific Reports  2016;6:30576.
Floral transition and petal onset, as two main aspects of flower development, are crucial to rapeseed evolutionary success and yield formation. Currently, very little is known regarding the genetic architecture that regulates flowering time and petal morphogenesis in Brassica napus. In the present study, a genome-wide transcriptomic analysis was performed with an absolutely apetalous and early flowering line, APL01, and a normally petalled line, PL01, using high-throughput RNA sequencing. In total, 13,205 differential expressed genes were detected, of which 6111 genes were significantly down-regulated, while 7094 genes were significantly up-regulated in the young inflorescences of APL01 compared with PL01. The expression levels of a vast number of genes involved in protein biosynthesis were altered in response to the early flowering and apetalous character. Based on the putative rapeseed flowering genes, an early flowering network, mainly comprised of vernalization and photoperiod pathways, was built. Additionally, 36 putative upstream genes possibly governing the apetalous character of line APL01 were identified, and six genes potentially regulating petal origination were obtained by combining with three petal-related quantitative trait loci. These findings will facilitate understanding of the molecular mechanisms underlying floral transition and petal initiation in B. napus.
doi:10.1038/srep30576
PMCID: PMC4962316  PMID: 27460760
23.  The Effect of Traditional Chinese Formula Danchaiheji on the Differentiation of Regulatory Dendritic Cells 
Recently, regulatory dendritic cells (DCregs), a newly described dendritic cell subset with potent immunomodulatory function, have attracted increased attention for their utility in treating immune response-related diseases, such as graft-versus-host disease, hypersensitivity, and autoimmune diseases. Danchaiheji (DCHJ) is a traditional Chinese formula that has been used for many years in the clinic. However, whether DCHJ can program dendritic cells towards a regulatory phenotype and the underlying mechanism behind this process remain unknown. Herein, we investigate the effects of traditional Chinese DCHJ on DCregs differentiation and a mouse model of skin transplantation. The current study demonstrates that DCHJ can induce dendritic cells to differentiate into DCregs, which are represented by high CD11b and low CD86 and HLA-DR expression as well as the secretion of IL-10 and TGF-β. In addition, DCHJ inhibited DC migration and T cell proliferation, which correlated with increased IDO expression. Furthermore, DCHJ significantly prolonged skin graft survival time in a mouse model of skin transplantation without any liver or kidney toxicity. The traditional Chinese formula DCHJ has the potential to be a potent immunosuppressive agent with high efficiency and nontoxicity.
doi:10.1155/2016/9179470
PMCID: PMC4976157  PMID: 27525028
24.  Direct Dry-Grinding Synthesis of Monodisperse Lipophilic CuS Nanoparticles 
Copper sulfide nanoparticles, effective absorbers of near-infrared light, are recently attracting broad interest as a photothermal coupling agent for cancer therapy. Lipophilic copper sulfide nanoparticles are preferred for high performance biomedical applications due to high tissue affinity. Synthesis of lipophilic copper sulfide nanoparticles requires complicated multi-step processes under severe conditions. Here, we describe a new synthetic process, developed by direct dry-grinding of copper(II) acetylacetonate with sulfur under ambient environment at low temperature. The formed CuS nanoparticles are of uniform size, ~10 nm in diameter, and are monodispersed in chloroform. Each covellite CuS nanocrystal surface is modified with oleylamine through hydrogen bonding between sulfur atoms and amine groups of oleylamine. The nanoparticles demonstrate near-infrared light absorption for photothermal applications. The synthetic methodology described here is more convenient and less extreme than previous methods, and should thus greatly facilitate the preparation of photothermal lipophilic copper sulfide nanomaterials for cancer therapy.
doi:10.1016/j.matchemphys.2015.06.041
PMCID: PMC4554346  PMID: 26339112
biomaterials; inorganic compounds; chemical synthesis; thermal properties
25.  Evolutionary features of thyroid cancer in patients with thyroidectomies from 2008 to 2013 in China 
Scientific Reports  2016;6:28414.
To evaluate the characteristics of thyroid carcinoma over time, we carried out a retrospective study to illustrate the evolutionary features of thyroid carcinoma. All records of thyroidectomies from the First Affiliated Hospital of Nanjing Medical University from 2008 to 2013 were obtained focusing on pathological diagnosis, size, local lymph node metastasis (LNM) of the tumors. The thyroid cancer detection rate increased from 24.6% to 41.5% significantly (P < 0.05). Papillary thyroid carcinoma (PTC) remained to be the most common type counting 86.4% of all thyroid carcinomas. In all 1,704 PTCs, microPTC (mPTC) with maximum diameter less than or equal to 10 mm has become the dominant form taking up 56.5% of all PTCs in 2013 while only 43.1% in 2008. The mean maximum tumor size has decreased from 17.8 mm to 12.2 mm significantly (P < 0.05). However, the average age, female dominance, and local LNM remained similarly in the past six years. Logistic regression test showed that the determinants for local LNM were age, gender and tumor size. mPTC has become the most common form of thyroid carcinoma detected during thyroidectomies in China while other features of thyroid carcinoma remained similarly in the recent years.
doi:10.1038/srep28414
PMCID: PMC4916471  PMID: 27328631

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