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2.  High performance platinum single atom electrocatalyst for oxygen reduction reaction 
Nature Communications  2017;8:15938.
For the large-scale sustainable implementation of polymer electrolyte membrane fuel cells in vehicles, high-performance electrocatalysts with low platinum consumption are desirable for use as cathode material during the oxygen reduction reaction in fuel cells. Here we report a carbon black-supported cost-effective, efficient and durable platinum single-atom electrocatalyst with carbon monoxide/methanol tolerance for the cathodic oxygen reduction reaction. The acidic single-cell with such a catalyst as cathode delivers high performance, with power density up to 680 mW cm−2 at 80 °C with a low platinum loading of 0.09 mgPt cm−2, corresponding to a platinum utilization of 0.13 gPt kW−1 in the fuel cell. Good fuel cell durability is also observed. Theoretical calculations reveal that the main effective sites on such platinum single-atom electrocatalysts are single-pyridinic-nitrogen-atom-anchored single-platinum-atom centres, which are tolerant to carbon monoxide/methanol, but highly active for the oxygen reduction reaction.
High-performance electrocatalysts for the oxygen reduction reaction (ORR) typically use platinum (Pt), however its high cost is a hindrance to commercial scale up. Here, the authors report a cost-effective, efficient and durable Pt single-atom electrocatalyst for ORR with a Pt utilization of 0.13 gPt kW−1 in a fuel cell.
doi:10.1038/ncomms15938
PMCID: PMC5527280  PMID: 28737170
3.  Transit times and mean ages for nonautonomous and autonomous compartmental systems 
Journal of Mathematical Biology  2016;73(6):1379-1398.
We develop a theory for transit times and mean ages for nonautonomous compartmental systems. Using the McKendrick–von Förster equation, we show that the mean ages of mass in a compartmental system satisfy a linear nonautonomous ordinary differential equation that is exponentially stable. We then define a nonautonomous version of transit time as the mean age of mass leaving the compartmental system at a particular time and show that our nonautonomous theory generalises the autonomous case. We apply these results to study a nine-dimensional nonautonomous compartmental system modeling the terrestrial carbon cycle, which is a modification of the Carnegie–Ames–Stanford approach model, and we demonstrate that the nonautonomous versions of transit time and mean age differ significantly from the autonomous quantities when calculated for that model.
doi:10.1007/s00285-016-0990-8
PMCID: PMC5061853  PMID: 27038163
Carbon cycle; CASA model; Compartmental system ; Exponential stability; Linear system; McKendrick–von Förster equation; Mean age; Nonautonomous dynamical system; Transit time; 34A30; 34D05
4.  Correlation between serum cystatin C level and elderly hypertensive patients combined coronary heart disease 
Objectives: To explore the correlation between serum cystatin C level and elderly hypertension with coronary heart disease patients. Methods: 500 hypertensive patients combined coronary heart disease were selected by coronary angiography. 321 of them were elderly patients with hypertension (male 204, female 117), and 400 of them were elderly patients with coronary heart disease (male 257, female 143), The serum cystatin C level of all patients were detected by immunoturbidimetry, and analyzed the correlation between the serum cystatin C level and different degree of blood pressure and the degree of coronary artery stenosis in elderly patients. Results: The serum cystatin C level was closely related with the blood pressure and the degree of the coronary artery stenosis. The higher the blood pressure level and the more serious the coronary artery stenosis, the higher the serum cystatin C level; The serum cystatin C level of hypertensive patients with coronary heart disease patients (Group D) were markedly higher than the level of the patients without hypertension and coronary heart disease patients (Group A), and the level of the patients with coronary heart disease (Group B) and the hypertension group (Group C) (P < 0.05). Conclusion: The serum cystatin C level of elderly patients with hypertension and coronary heart disease were closely related with the degree of blood pressure and coronary arteries stenosis. The serum cystatin C maybe a predictor of disease severity in elderly hypertensive patients with coronary heart disease.
PMCID: PMC4483934  PMID: 26131241
Cystatin C; elderly patients; hypertension; coronary artery disease; correlation
5.  Genome Sequence of Phytophthora fragariae var. fragariae, a Quarantine Plant-Pathogenic Fungus 
Genome Announcements  2015;3(2):e00034-15.
Phytophthora fragariae var. fragariae is a serious plant-pathogenic fungus causing red core disease in strawberries, resulting in a larger number of fruit produced, and the fungus has been regulated as a quarantine pest of many countries and regions. Here, we announce the genome sequence of P. fragariae var. fragariae, and this information might provide insight into the mechanism of pathogenicity and host specificity of this pathogen, as well as help us further identify targets for fungicides.
doi:10.1128/genomeA.00034-15
PMCID: PMC4384129  PMID: 25814589
6.  Effect of Dan Hong injection on PON1, SOD activity and MDA levels in elderly patients with coronary heart disease 
Objective: To research the effect of Dan Hong injection (DHI) on PON1, SOD activity and MDA levels in elderly patients with coronary heart disease (CHD). Methods: 98 elderly patients with CHD diagnosed by coronary angiography were randomly divided into conventional treatment group and DHI treatment group, measured and analysis the serum PON1 activity, SOD and MDA levels before and after treatment in the two groups. Results: PON1 and SOD activity in elderly CHD patients were significantly lower than elderly non-coronary heart disease group, there was a significant difference between the two groups (P < 0.01); and MDA level in elderly CHD patients was significantly higher than elderly non-coronary heart disease group, there was a significant difference between the two groups (P < 0.01). There was a major change in PON1 activity, SOD and MDA after 4 weeks DHI treatment (P < 0.05). There was different degrees of change in PON activity, SOD and MDA after 4 weeks conventional treatment when compared with pre-administer DHI, but did not reach significant difference (P > 0.05); PON1 activity, SOD and MDA had significant different after 4 weeks treatment in DHI group compared with the conventional treatment group (P < 0.05). Conclusions: There is lipid peroxidation in the elderly patients with the coronary heart disease. DHI can raise serum PON1, SOD activity and lower MDA to improve the antioxidant effect in elderly patients with coronary heart disease.
PMCID: PMC4307573  PMID: 25664126
Dan Hong injection; elderly; coronary heart disease; paraoxonase; malondialdehyde; superoxide dismutase; lipid peroxidation
7.  Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits 
PLoS ONE  2014;9(11):e111215.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.
doi:10.1371/journal.pone.0111215
PMCID: PMC4227681  PMID: 25386946
8.  Chronic myelomonocytic leukemia with double-mutations in DNMT3A and FLT3-ITD treated with decitabine and sorafenib 
Cancer Biology & Therapy  2017;18(11):843-849.
ABSTRACT
Chronic myelomonocytic leukemia (CMML) is a heterogeneous neoplastic hematologic disorder with worse overall survival. Half of CMML have mutations, but case with concomitant mutations of DNA methyltransferase 3A (DNMT3A) and Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3-ITD) in CMML was not reported before. We reported a 51-year-old man who had CMML with concomitant mutations in DNMT3A and FLT3-ITD.The patient received decitabine and sorafenib combined treatment. In this report, we reviewed DNMT3A mutation and FLT3 mutation, and we reviewed treatment of decitabine and sorafenib. This report is significant. First: This is the first report on CMML with double-mutations of DNMT3A and FLT3-ITD. Second: It shows the importance of targeted drug in combined treatment of CMML.
doi:10.1080/15384047.2017.1281491
PMCID: PMC5710697  PMID: 28102729
CMML; DNMT3A; double-mutations; FLT3-ITD; sorafenib
9.  Authentication of M14 melanoma cell line proves misidentification of MDA‐MB‐435 breast cancer cell line 
International Journal of Cancer  2017;142(3):561-572.
A variety of analytical approaches have indicated that melanoma cell line UCLA‐SO‐M14 (M14) and breast carcinoma cell line MDA‐MB‐435 originate from a common donor. This indicates that at some point in the past, one of these cell lines became misidentified, meaning that it ceased to correspond to the reported donor and instead became falsely identified (through cross‐contamination or other means) as a cell line from a different donor. Initial studies concluded that MDA‐MB‐435 was the misidentified cell line and M14 was the authentic cell line, although contradictory evidence has been published, resulting in further confusion. To address this question, we obtained early samples of the melanoma cell line (M14), a lymphoblastoid cell line from the same donor (ML14), and donor serum preserved at the originator's institution. M14 samples were cryopreserved in December 1975, before MDA‐MB‐435 cells were established in culture. Through a series of molecular characterizations, including short tandem repeat (STR) profiling and cytogenetic analysis, we demonstrated that later samples of M14 and MDA‐MB‐435 correspond to samples of M14 frozen in 1975, to the lymphoblastoid cell line ML14, and to the melanoma donor's STR profile, sex and blood type. This work demonstrates conclusively that M14 is the authentic cell line and MDA‐MB‐435 is misidentified. With clear provenance information and authentication testing of early samples, it is possible to resolve debates regarding the origins of problematic cell lines that are widely used in cancer research.
What's new?
A variety of analytical approaches have indicated that melanoma cell line M14 and breast carcinoma cell line MDA‐MB‐435 originate from a common donor, but there is ongoing debate regarding which is the misidentified cell line. Here, authentication testing of M14 from 1975 (prior to the establishment of MDA‐MB‐435), with comparison to donor serum and lymphoblastoid cell line ML14, shows that M14 is the authentic cell line and MDA‐MB‐435 is a misidentified derivative. With clear provenance information and authentication testing of early samples, debates regarding the origins of problematic cell lines that are widely used in cancer research can be resolved.
doi:10.1002/ijc.31067
PMCID: PMC5762610  PMID: 28940260
authentication; cross‐contamination; human cell lines; misidentification; STR profiling
12.  Conjugation of φBT1-derived integrative plasmid pDZL802 in Amycolatopsis mediterranei U32 
Bioengineered  2017;8(5):549-554.
ABSTRACT
The genus Amycolatopsis is well known for its ability to produce antibiotics, and an increasing number of valuable biotechnological applications, such as bioremediation, biodegradation, bioconversion, and potentially biofuel, that use this genus have been developed. Amycolatopsis mediterranei is an industrial-scale producer of the important antibiotic rifamycin, which plays a vital role in antimycobacterial therapy. Genetic studies of Amycolatopsis species have progressed slowly due to the lack of efficient transformation methods and stable plasmid vectors. In A. mediterranei U32, electroporation and replicable plasmid vectors have been developed. Here, we establish a simple and efficient conjugal system by transferring integrative plasmid pDZL802 from ET12567 (pUZ8002) to A. mediterranei U32, with an efficiency of 4 × 10−5 CFU per recipient cell. This integrative vector, based on the φBT1 int-attP locus, is a stable and versatile tool for A. mediterranei U32, and it may also be applicable to various other Amycolatopsis species for strain improvement, heterologous protein expression, and synthetic biology experiments.
doi:10.1080/21655979.2016.1270808
PMCID: PMC5639847  PMID: 28045587
Amycolatopsis; conjugal transfer system; integrative plasmid; metabolic engineering; natural products
13.  Correlation of transient adenosine release and oxygen changes in the caudate-putamen 
Journal of neurochemistry  2016;140(1):13-23.
Adenosine is an endogenous nucleoside that modulates important physiological processes, such as vasodilation, in the central nervous system. A rapid, 2–4 seconds, mode of adenosine signaling has been recently discovered, but the relationship between this type of adenosine and blood flow change has not been characterized. In this study, adenosine and oxygen changes were simultaneously measured using fast-scan cyclic voltammetry. Oxygen changes occur when there is an increase in local cerebral blood flow and thus are a measure of vasodilation. About 34% of adenosine transients in the rat caudate-putamen are correlated with a subsequent transient change in oxygen. The amount of oxygen was correlated with the concentration of adenosine release and larger adenosine transients (over 0.4 μM) always had subsequent oxygen changes. The average duration of adenosine and oxygen transients were 3.2 seconds and 3.5 seconds, respectively. On average, the adenosine release starts and peaks 0.2 seconds prior to the oxygen. The A2a antagonist, SCH442416, decreased the number of both adenosine and oxygen transient events by about 32%. However, the A1 antagonist, DPCPX, did not significantly affect simultaneous adenosine and oxygen release. The nitric oxide (NO) synthase inhibitor L-NAME also did not affect the concentration or number of adenosine and oxygen release events. These results demonstrate that both adenosine and oxygen release are modulated via A2a receptors. The correlation of transient concentrations, time delay between adenosine and oxygen peaks, and effect of A2a receptors suggests adenosine modulates blood flow on a rapid, sub-second time scale.
doi:10.1111/jnc.13705
PMCID: PMC5164875  PMID: 27314215
Adenosine; Oxygen; in vivo; blood flow; Fast scan cyclic voltammetry; FSCV
14.  Antidepressant‐like effects of fenofibrate in mice via the hippocampal brain‐derived neurotrophic factor signalling pathway 
British Journal of Pharmacology  2016;174(2):177-194.
Background and Purpose
Depression is a neuropsychiatric disorder accompanied by a decrease in the brain‐derived neurotrophic factor (BDNF) signalling cascade in the hippocampus. Fenofibrate is a selective agonist of PPAR‐α. In this study, we investigated the antidepressant‐like effects of fenofibrate in C57BL/6J mice.
Experimental Approach
The antidepressant‐like effects of fenofibrate were first identified in the forced swim test (FST) and tail suspension test (TST), and then assessed in the chronic social defeat stress (CSDS) model. The changes in the hippocampal BDNF signalling pathway and adult hippocampal neurogenesis after CSDS and fenofibrate treatment were further investigated. A PPAR‐α inhibitor, cannabinoid system inhibitors and BDNF signalling inhibitors were also used to determine the antidepressant mechanisms of fenofibrate.
Key Results
Fenofibrate administration exhibited antidepressant‐like effects in the FST and TST without affecting the locomotor activity of mice. Chronic fenofibrate treatment also prevented the depressive‐like symptoms induced by CSDS. Moreover, fenofibrate restored the CSDS‐induced decrease in the hippocampal BDNF signalling cascade and adult hippocampal neurogenesis. The antidepressant‐like effects of fenofibrate could be blocked by a PPAR‐α inhibitor and BDNF signalling inhibitors.
Conclusions and Implications
Taken together, these results suggest that fenofibrate has antidepressant‐like effects mediated through the promotion of the hippocampal BDNF signalling cascade.
doi:10.1111/bph.13668
PMCID: PMC5192965  PMID: 27861729
15.  A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway 
Theranostics  2018;8(2):549-562.
Rationale: Monoclonal antibodies (mAbs) mostly targeting extracellular or cell surface molecules have been widely used in the treatment of various diseases. However, mAbs cannot pass through the cell membrane as efficiently as small compounds, thus limiting their use against intracellular targets. Methods to shuttle antibodies into living cells may largely expand research and application in areas based on mAbs. Hepatitis B virus X protein (HBx) is an important intracellular multi-functional viral protein in the life cycle of hepatitis B virus (HBV). HBx plays essential roles in virus infection and replication and is strongly associated with HBV-related carcinogenesis.
Methods: In this study, we developed a cell-penetrating whole molecule antibody targeting HBx (9D11-Tat) by the fusion of a cell penetrating peptide (CPP) on the C-terminus of the heavy chain of a potent mAb specific to HBx (9D11). The anti-HBV effect and mechanism of 9D11-Tat were investigated in cell and mouse models mimicking chronic HBV infection.
Results: Our results demonstrated that the recombinant 9D11-Tat antibody could efficiently internalize into living cells and significantly suppress viral transcription, replication, and protein production both in vitro and in vivo. Further analyses suggested the internalized 9D11-Tat antibody could greatly reduce intracellular HBx via Fc binding receptor TRIM21-mediated protein degradation. This process simultaneously stimulated the activations of NF-κB, AP-1, and IFN-β, which promoted an antiviral state of the host cell.
Conclusion: In summary, our study offers a new approach to target intracellular pathogenesis-related protein by engineered cell-penetrating mAb expanding their potential for therapeutic applications. Moreover, the 9D11-Tat antibody may provide a novel therapeutic agent against human chronic HBV infection.
doi:10.7150/thno.20047
PMCID: PMC5743566
antibodies for intracellular targets; cell-penetrating peptide; antibody-mediated intracellular immunity; hepatitis B virus; Hepatitis B virus X protein
16.  Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling 
Theranostics  2018;8(3):627-643.
Low density lipoprotein receptor-related protein 6 (LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood.
Methods: We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice.
Results: Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group. Tamoxifen-inducible cardiac-specific LRP6 knockout mice developed acute heart failure and mitochondrial dysfunction with reduced survival. Proteomic analysis suggests the fatty acid metabolism disorder involving peroxisome proliferator-activated receptors (PPARs) signaling in the LRP6 deficient heart. Accumulation of mitochondrial targeting to autophagosomes and lipid droplet were observed in LRP6 deletion hearts. Further analysis revealed cardiac LRP6 deletion suppressed autophagic degradation and fatty acid utilization, coinciding with activation of dynamin-related protein 1 (Drp1) and downregulation of nuclear TFEB (Transcription factor EB). Injection of Mdivi-1, a Drp1 inhibitor, not only promoted nuclear translocation of TFEB, but also partially rescued autophagic degradation, improved PPARs signaling, and attenuated cardiac dysfunction induced by cardiac specific LRP6 deletion.
Conclusions: Cardiac LRP6 deficiency greatly suppressed autophagic degradation and fatty acid utilization, and subsequently leads to lethal dilated cardiomyopathy and cardiac dysfunction through activation of Drp1 signaling. It suggests that heart failure progression may be attenuated by therapeutic modulation of LRP6 expression.
doi:10.7150/thno.22177
PMCID: PMC5771081
LRP6; Autophagy; Heart failure; mTOR; TFEB
17.  Immunotherapy of patient with hepatocellular carcinoma using cytotoxic T lymphocytes ex vivo activated with tumor antigen-pulsed dendritic cells 
Journal of Cancer  2018;9(2):275-287.
Purpose The aim of this study was to evaluate the clinical response of immunotherapy with dendritic cell-cytotoxic T lymphocytes (DC-CTLs) in patients with hepatocellular carcinoma (HCC).
Method Sixty-eight patients with a confirmed diagnosis of HCC and who received follow-up until December 2015 were enrolled. We measured immune phenotypes of DCs and activated T cells using flow cytometry and clinical indexes using an electrochemiluminescence method.
Results DCs exhibited up-regulation of the maturation markers CD83, CD80, CD11c, and CD86 on day8. Levels of IFN-γ and TNF-α were higher in the DCs pulsed with tumor-associated antigens (TAAs) than in DCs with a non-proliferative recombinant adenovirus. The percentage of regulatory T cells (Tregs) decreased in patients after DC-CTLs therapy. In addition, serum levels of AFP, AFP-L3, ALT, and CA19-9 were significantly reduced in these patients. Quality of life was improved, especially on physical functioning scales. Median overall survival (OS) and progression-free survival (PFS) were 8.2 months and 4.3 months, respectively, for the control group and 12.8 months and 9 months, respectively, for the DC-CTL group. Patients treated with DC-CTLs therapy showed a statistically significant PFS and OS curve (OS: p=0.016; PFS: p<0.0001). In addition, no serious adverse reactions were observed.
Conclusion This study indicated that Tregs, as well as serum levels of AFP, AFP-L3, ALT, and CA19-9, which were correlated with a poor prognosis, decreased after DC-CTL treatments. The OS, PFS and the quality of life of HCC patients partially improved.
doi:10.7150/jca.22176
PMCID: PMC5771335
Dendritic cell-cytotoxic T lymphocyte; immunotherapy; Treg; quality of life.
18.  Nε-carboxymethyl-lysine promotes calcium deposition in VSMCs via intracellular oxidative stress-induced PDK4 activation and alters glucose metabolism 
Oncotarget  2017;8(68):112841-112854.
Diabetes and vascular calcification are intrinsically linked. We previously reported that advanced glycation end products (AGEs) accelerate calcium deposition in vascular smooth muscle cells (VSMCs) via excessive oxidative stress. However, the underlying mechanism remains poorly understood. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy metabolism. Since hyperactivation of PDK4 has been reported in calcified vessels and in patients with diabetes mellitus, inhibition of PDK4 expression may be a strategy for the prevention of diabetic vascular calcification. In this study, we used a rat VSMC model to investigate the role of PDK4 in diabetic vascular calcification and further explore the underlying mechanisms. We observed that Nε-carboxymethyl-lysine (CML), which is a major immunogen of AGEs, accelerated calcium deposition in VSMCs through PDK4 activation. An elevated level of reactive oxygen species (ROS) acted as a signal transduction intermediate to increase PDK4 expression. Either inhibition of PDK4 expression or RAGE (receptor for AGEs) blockade attenuated CML-induced VSMC calcification, as shown by decreased alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression. Glucose consumption and lactate production were increased during CML-induced VSMC calcification. Importantly, CML accelerates glycolysis in VSMCs via a PDK4-dependent pathway. In conclusion, this study demonstrates a novel mechanism by which CML promotes VSMC calcification via PDK4 activation and alters glucose metabolism in VSMCs.
doi:10.18632/oncotarget.22835
PMCID: PMC5762555
PDK4; CML; calcification; oxidative stress; glycolysis
19.  Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC 
BMC Cancer  2017;17:884.
Background
The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim.
Methods
The patients were treated with the vaccine at 1 × 106, 1 × 107and the maximum dose 8 × 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life.
Results
The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients’quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence.
Conclusions
We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients’ quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.
doi:10.1186/s12885-017-3859-3
PMCID: PMC5740508  PMID: 29268708
Modified-DCvaccine; Non-small cell lung cancer (NSCLC); Phase I clinical trial
20.  De novo assembly and comparative analysis of the transcriptome of embryogenic callus formation in bread wheat (Triticum aestivum L.) 
BMC Plant Biology  2017;17:244.
Background
During asexual reproduction the embryogenic callus can differentiate into a new plantlet, offering great potential for fostering in vitro culture efficiency in plants. The immature embryos (IMEs) of wheat (Triticum aestivum L.) are more easily able to generate embryogenic callus than mature embryos (MEs). To understand the molecular process of embryogenic callus formation in wheat, de novo transcriptome sequencing was used to generate transcriptome sequences from calli derived from IMEs and MEs after 3d, 6d, or 15d of culture (DC).
Results
In total, 155 million high quality paired-end reads were obtained from the 6 cDNA libraries. Our de novo assembly generated 142,221 unigenes, of which 59,976 (42.17%) were annotated with a significant Blastx against nr, Pfam, Swissprot, KOG, KEGG, GO and COG/KOG databases. Comparative transcriptome analysis indicated that a total of 5194 differentially expressed genes (DEGs) were identified in the comparisons of IME vs. ME at the three stages, including 3181, 2085 and 1468 DEGs at 3, 6 and 15 DC, respectively. Of them, 283 overlapped in all the three comparisons. Furthermore, 4731 DEGs were identified in the comparisons between stages in IMEs and MEs. Functional analysis revealed that 271transcription factor (TF) genes (10 overlapped in all 3 comparisons of IME vs. ME) and 346 somatic embryogenesis related genes (SSEGs; 35 overlapped in all 3 comparisons of IME vs. ME) were differentially expressed in at least one comparison of IME vs. ME. In addition, of the 283 overlapped DEGs in the 3 comparisons of IME vs. ME, excluding the SSEGs and TFs, 39 possessed a higher rate of involvement in biological processes relating to response to stimuli, in multi-organism processes, reproductive processes and reproduction. Furthermore, 7 were simultaneously differentially expressed in the 2 comparisons between the stages in IMEs, but not MEs, suggesting that they may be related to embryogenic callus formation. The expression levels of genes, which were validated by qRT-PCR, showed a high correlation with the RNA-seq value.
Conclusions
This study provides new insights into the role of the transcriptome in embryogenic callus formation in wheat, and will serve as a valuable resource for further studies addressing embryogenic callus formation in plants.
Electronic supplementary material
The online version of this article (10.1186/s12870-017-1204-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-017-1204-2
PMCID: PMC5735865  PMID: 29258440
Transcriptome; Embryo culture; Embryogenic callus; Immature embryo; Mature embryo; Wheat (Triticum aestivum L.)
21.  Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals 
Oncotarget  2017;8(67):111144-111160.
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy that is often resistant to therapy. Nowadays, chemotherapy is still one of the main methods for the treatment of ESCC. However, the multidrug resistance (MDR)-mediated chemotherapy resistance is one of the leading causes of death. Exploring agents able to reverse MDR, which thereby increase the sensitivity with clinical first-line chemotherapy drugs, could significantly improve cancer treatment. Cepharanthine hydrochloride (CEH) has the ability to reverse the MDR in ESCC and the mechanism involved have not been reported. The aim of the study was to investigate the potential of CEH to sensitize chemotherapeutic drugs in ESCC and explore the underlying mechanisms by in vitro and in vivo studies. Our data demonstrated that CEH significantly inhibited ESCC cell proliferation in a dose-dependent manner, induced G2/M phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to cisplatin (cDDP). Mechanistically, CEH inhibited ESCC cell growth and induced apoptosis through activation of c-Jun, thereby inhibiting the expression of P-gp, and enhancing p21 expression via activation of the p53 signaling pathway. In this study, we observed that growth of xenograft tumors derived from ESCC cell lines in nude mice was also significantly inhibited by combination therapy. To our knowledge, we demonstrate for the first time that CEH is a potentially effective MDR reversal agent for ESCC, based on downregulation of the mRNA expression of MDR1 and P-gp. Together, these results reveal emphasize CEH putative role as a resistance reversal agent for ESCC.
doi:10.18632/oncotarget.22676
PMCID: PMC5762312
cepharanthine hydrochloride; multi-drug resistance; MDR1; p-53; c-Jun/JNK
22.  Scientometric analysis of published papers in global ophthalmology in the past ten years 
International Journal of Ophthalmology  2017;10(12):1898-1901.
AIM
To investigate the published papers of ophthalmology in past ten years and explore the development of ophthalmology.
METHORDS
The data of this study retrieved from Science Citation Index Expanded and downloaded online in November 2017, including all the papers with publication year from 2007-2016 were analyzed. The papers were based on the Web of Science category and the journals were based on the Journal Citation Report category.
RESULTS
The number of ophthalmology papers increased from 7450 to 9089 during 2007 to 2017. The average rate increased 2.2% annually. USA accounts for one thirds of the total and two thirds of the highly cited papers. In Asia, China, Japan and South Korea were in Top 10 by the number of ophthalmology papers. UK, Germany, Japan and Australia also had great impact in global ophthalmology. The hot spots included endothelial growth factor, optical coherence tomography and open-angle glaucoma.
CONCLUSION
USA is in the leading position in global ophthalmology. Part of Asian countries play an important role in the development of ophthalmology, but the impact needs to be improved.
doi:10.18240/ijo.2017.12.17
PMCID: PMC5733519
ophthalmology; evaluation; scientometrics
23.  Targeted bisulfite sequencing identified a panel of DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC) 
Clinical Epigenetics  2017;9:129.
Background
DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. However, limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC).
Methods
A high-throughput DNA methylation dataset (100 samples) of ESCC from The Cancer Genome Atlas (TCGA) project was analyzed and validated along with another independent dataset (12 samples) from the Gene Expression Omnibus (GEO) database. The methylation status of peripheral blood mononuclear cells and peripheral blood leukocytes from healthy controls was also utilized for biomarker selection. The candidate CpG sites as well as their adjacent regions were further validated in 94 pairs of ESCC tumor and adjacent normal tissues from the Chinese Han population using the targeted bisulfite sequencing method. Logistic regression and several machine learning methods were applied for evaluation of the diagnostic ability of our panel.
Results
In the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 × 10−4; cg19396867, P = 3.60 × 10−4; cg20655070, P = 3.60 × 10−4; cg26671652, P = 5.77 × 10−4; and cg27062795, P = 3.60 × 10−4. In the validation stage, the methylation status of both the five CpG sites and their adjacent genomic regions were tested. The diagnostic model based on the combination of these five genomic regions yielded a robust performance (sensitivity = 0.75, specificity = 0.88, AUC = 0.85). Eight statistical models along with five-fold cross-validation were further applied, in which the SVM model reached the best accuracy in both training and test dataset (accuracy = 0.82 and 0.80, respectively). In addition, subgroup analyses revealed a significant difference in diagnostic performance between the alcohol use and non-alcohol use subgroups.
Conclusions
Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.
Electronic supplementary material
The online version of this article (10.1186/s13148-017-0430-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-017-0430-7
PMCID: PMC5732523  PMID: 29270239
Esophageal squamous cell carcinoma; DNA methylation; Biomarker; Diagnosis; Targeted bisulfite sequencing
24.  C21 steroid-enriched fraction refined from Marsdenia tenacissima inhibits hepatocellular carcinoma through the coordination of Hippo-Yap and PTEN-PI3K/AKT signaling pathways 
Oncotarget  2017;8(66):110576-110591.
Marsdenia tenacissimae extraction (MTE), a traditional herbal medicine, has exhibited anti-tumor effects on a variety of cancers. However, its effectiveness and the mechanism of action in Hepatocellular carcinoma (HCC) has not been fully understood. In the present study, we demonstrate that C21 steroid-enriched fraction from MTE, which contains five main C21 steroids (FR5) exhibits obvious pharmacological activities on HCC cells in vitro and in vivo. FR5 induces apoptosis and inhibits proliferation and migration of HepG2 and Bel7402 cells in a dose and time dependent manner. Furthermore, in HCC cells, we found that FR5 inhibits Hippo pathway, leading to inactivation of YAP and increase of PTEN. Enhanced PTEN results in the inhibition of PI3K/AKT signaling pathway, inhibiting cell proliferation by FR5 and FR5-induced apoptosis. Moreover, it was proved that FR5 treatment could inhibit tumor growth in a HCC xenograft mouse model, and immunohistochemistry results showed FR5 treatment resulted in down-regulation of Bcl-2 and YAP, and up-regulation of PTEN and PI3K. Taken together, we found that FR5 effectively inhibits proliferation and induces apoptosis of HCC cells through coordinated inhibition of YAP in the Hippo pathway and AKT in the PI3K-PTEN-mTOR pathway, and suggest FR5 as a potential therapy for HCC.
doi:10.18632/oncotarget.22833
PMCID: PMC5746405
hepatocellular carcinoma; Marsdenia tenacissima; Hippo-YAP signaling pathway; PI3K/AKT signaling pathway; C21 steroids
25.  Histones are rapidly loaded onto unintegrated retroviral DNAs soon after nuclear entry 
Cell host & microbe  2016;20(6):798-809.
Summary
Chromosomal structure of nuclear DNA is usually maintained by insertion of nucleosomes into preexisting chromatin, both on newly synthesized DNA at replication forks and at sites of DNA damage. But during retrovirus infection, a histone-free DNA copy of the viral genome is synthesized that must be loaded with nucleosomes de novo. Here we show that core histones are rapidly loaded onto unintegrated Moloney murine leukemia virus DNAs. Loading of nucleosomes requires nuclear entry but does not require viral DNA integration. The histones associated with unintegrated DNAs become marked by covalent modifications, with a delay relative to the time of core histone loading. Expression from unintegrated DNA can be enhanced by modulation of the histone modifying machinery. The data show that histone loading onto unintegrated DNAs occurs very rapidly after nuclear entry and does not require prior establishment of an integrated provirus.
Graphical abstract
doi:10.1016/j.chom.2016.10.009
PMCID: PMC5159289  PMID: 27866901
Retrovirus; Nucleosome; Histone; Epigenetics

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