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1.  γ-secretase inhibitor up-regulates vascular endothelial growth factor receptor-2 and endothelial nitric oxide synthase 
Although previous studies have shown that γ-secretase inhibitors significantly suppress tumor growth via anti-angiogenesis, the mechanism involved in the regulation of tumor angiogenesis by γ-secretase inhibitors has not been clearly understood. The objective of this study was to investigate the regulation of vascular endothelial growth factor receptor (VEGFR) and endothelial nitric oxide synthase (eNOS) by a γ-secretase inhibitor in the H5V mouse microvascular endothelial cell line. H5V cells were cultured with different concentrations of the γ-secretase inhibitor DAPT for 48 h and with 100 μmol/l DAPT at different incubation times. Protein and mRNA expression of VEGFR-1, VEGFR-2, VEGFR-3 and eNOS was measured by Western blotting and real-time PCR, respectively. The VEGFR-2 kinase inhibitor was used to assess the role of VEGFR-2 in eNOS regulation. We found that the γ-secretase inhibitor DAPT increased protein and mRNA expression of VEGFR-2 and eNOS, but decreased VEGFR-1 expression and had no significant effect on VEGFR-3. Up-regulation of eNOS was blocked by the VEGFR-2 kinase inhibitor. In conclusion, the γ-secretase inhibitor enhances VEGFR-2 and eNOS expression, and the up-regulation of eNOS is dependent on an increase in VEGFR-2. Thus, we suggest that administration of the γ-secretase inhibitor be combined with disruption of eNOS or interruption of VEGF signaling, which may improve the anti-angiogenic efficacy in tumor treatments.
PMCID: PMC3440738  PMID: 22977566
angiogenesis; vascular endothelial growth factor receptor; endothelial nitric oxide synthase
2.  Knee Society Award Papers Are Highly Cited Works 
Since 1993, The Knee Society has presented three annual awards recognizing the best research papers presented at the annual meetings. To date, no quantitative evaluation has determined whether the selection process identifies the most meritorious papers based on subsequent citations. In the absence of validation of this process, it is unclear whether the journal readership should view the award-winning papers as those with potentially greater impact for the specialty.
(1) Are award papers cited both more than nonaward papers published in the same Knee Society proceedings issue of CORR® and more than all other knee research papers published in all issues of CORR® during any given year? (2) Does the award selection process identify potentially highly influential knee research?
Subsequent citations for each award and nonaward paper published in The Knee Society proceedings issue for 2002 to 2008 were determined using the SCOPUS citation index. The citations for all papers on knee surgery published in CORR® during the same years were also determined.
Mean citations for an award paper were statistically greater than for a nonaward paper: 86 (SD 95; median 55; 95% confidence interval [CI] of the mean, 44–128) versus 33 (SD 30; median 24; 95% CI of the mean, 28–37; p < 0.001). Mean number of citations for award papers was also higher than for all other knee research papers published in nonproceedings issues of CORR®: 86 (SD 95; median 55; 95% CI of the mean, 44–128) versus 30 (SD 31; median 20; 95% CI for the mean, 25–35; p < 0.001). Twelve of the 22 (54.6%) award papers were in the top five cited papers from the proceedings issue for the respective year versus 24 of the 190 (12.6%) of the nonaward papers (difference in the percentages is 41.9% and the 95% CI for the risk difference is 20.6%–63.3%; p < 0.001). In 3 of 7 years, an award paper was the most cited knee paper published in CORR®.
The selection process for The Knee Society scientific awards identifies potentially influential papers that are likely to be highly cited in future research articles about the knee.
Clinical Relevance
The selection process for Knee Society Award Papers appears to identify papers that are potentially influential in the field of knee surgery and are likely to be highly cited in future published articles. As such, these award papers deserve special attention from the readership.
PMCID: PMC4686501  PMID: 26013147
3.  A chromosome-level genome assembly of the Asian arowana, Scleropages formosus 
Scientific Data  2016;3:160105.
Asian arowana (Scleropages formosus), an ancient teleost belonging to the Order Osteoglossomorpha, has been a valuable ornamental fish with some varieties. However, its biological studies and breeding germplasm have been remarkably limited by the lack of a reference genome. To solve these problems, here we report high-quality genome sequences of three common varieties of Asian arowana (the golden, red and green arowana). We firstly generated a chromosome-level genome assembly of the golden arowana, on basis of the genetic linkage map constructed with the restriction site-associated DNA sequencing (RAD-seq). In addition, we obtained draft genome assemblies of the red and green varieties. Finally, we annotated 22,016, 21,256 and 21,524 protein-coding genes in the genome assemblies of golden, red and green varieties respectively. Our data were deposited in publicly accessible repositories to promote biological research and molecular breeding of Asian arowana.
PMCID: PMC5139669  PMID: 27922628
Genome; Bioinformatics; DNA sequencing; Ichthyology
4.  Endostatin’s Emerging Roles in Angiogenesis, Lymphangiogenesis, Disease, and Clinical Applications 
Biochimica et biophysica acta  2015;1850(12):2422-2438.
Angiogenesis is the process of neovascularization from pre-existing vasculature and is involved in various physiological and pathological processes. Inhibitors of angiogenesis, administered either as individual drugs or in combination with other chemotherapy, have been shown to benefit patients with various cancers. Endostatin, a 20-kDa C-terminal fragment of type XVIII collagen, is one of the most potent inhibitors of angiogenesis.
Scope of review
We discuss the biology behind endostatin in the context of its endogenous production, the various receptors to which it binds, and the mechanisms by which it acts. We focus on its inhibitory role in angiogenesis, lymphangiogenesis, and cancer metastasis. We also present emerging clinical applications for endostatin and its potential as a therapeutic agent in the form a short peptide.
Major conclusions
The delicate balance between pro- and anti-angiogenic factors can be modulated to result in physiological wound healing or pathological tumor metastasis. Research in the last decade has emphasized an emerging clinical potential for endostatin as a biomarker and as a therapeutic short peptide. Moreover, elevated or depressed endostatin levels in diseased states may help explain the pathophysiological mechanisms of the particular disease.
General significance
Endostatin was once sought after as the ‘be all and end all’ for cancer treatment; however, research throughout the last decade has made it apparent that endostatin’s effects are complex and involve multiple mechanisms. A better understanding of newly discovered mechanisms and clinical applications still has the potential to lead to future advances in the use of endostatin in the clinic.
PMCID: PMC4624607  PMID: 26367079
Matricryptin; Tumor angiogenesis; Type XVIII collagen; Anti-angiogenic factor; MMP; Short endostatin peptide
5.  Protective effects of resveratrol on autologous nucleus pulposus model of radiculopathy 
Nucleus pulposus (NP) has been suggested to trigger an autoimmune response if exposed to the immune system, which plays a key role in neuropathic pain. Therefore, appropriate suppression of inflammation is a key factor for treating the radiculopathy caused by intervertebral disk (IVD) degeneration. Resveratrol, a key component of red wine, has been suggested to exhibit anti-inflammatory properties in vitro and in vivo. However, the effects of resveratrol on NP-mediated pain in vivo have not been studied. The aim of the present study was to investigate whether resveratrol may be useful in treating NP-mediated pain in an autologous NP model of radiculopathy. A total of 36 adult male Sprague-Dawley rats were allocated randomly into sham (group I), saline-treated (group II) and resveratrol-treated (group III) groups. Animal behavior in response to non-noxious mechanical stimulation with von Frey filaments was compared at days 0 (baseline), 3, 7, 14 and 21 following surgery. The expression of proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) were assessed at days 7 and 14. The data showed that resveratrol exhibited an anti-inflammatory effect on the expression of proinflammatory cytokines. Compared with group II, the expression of TNF-α and IL-1 was significantly decreased at each time point in group III. In addition, resveratrol significantly reduced pain behavior triggered by the application of NP tissue on the dorsal root ganglion for up to 14 days. These data suggest that resveratrol has potential for the treatment of NP-mediated pain, indicating a potential clinical application.
PMCID: PMC5228059
resveratrol; anti-inflammatory; nucleus pulposus-mediated back pain; radiculopathy
6.  Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis 
PLoS ONE  2016;11(11):e0165290.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are related to the immune response. Genes—toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), interleukin-1β (IL-1β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 1 (CXCL1)—related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs) and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS.
PMCID: PMC5094695  PMID: 27812125
7.  A Comparison of Cough Assistance Techniques in Patients with Respiratory Muscle Weakness 
Yonsei Medical Journal  2016;57(6):1488-1493.
To assess the ability of a mechanical in-exsufflator (MI-E), either alone or in combination with manual thrust, to augment cough in patients with neuromuscular disease (NMD) and respiratory muscle dysfunction.
Materials and Methods
For this randomized crossover single-center controlled trial, patients with noninvasive ventilator-dependent NMD were recruited. The primary outcome was peak cough flow (PCF), which was measured in each patient after a cough that was unassisted, manually assisted following a maximum insufflation capacity (MIC) maneuver, assisted by MI-E, or assisted by manual thrust plus MI-E. The cough augmentation techniques were provided in random order. PCF was measured using a new device, the Cough Aid.
All 40 enrolled participants (37 males, three females; average age, 20.9±7.2 years) completed the study. The mean (standard deviation) PCFs in the unassisted, manually assisted following an MIC maneuver, MI-E-assisted, and manual thrust plus MI-E-assisted conditions were 95.7 (40.5), 155.9 (53.1), 177.2 (33.9), and 202.4 (46.6) L/min, respectively. All three interventions significantly improved PCF. However, manual assistance following an MIC maneuver was significantly less effective than MI-E alone. Manual thrust plus MI-E was significantly more effective than both of these interventions.
In patients with NMD and respiratory muscle dysfunction, MI-E alone was more effective than manual assistance following an MIC maneuver. However, MI-E used in conjunction with manual thrust improved PCF even further.
PMCID: PMC5011283  PMID: 27593879
Neuromuscular disease; peak cough flow; cough augmentation; mechanical in-exsufflator
8.  Virtual surgical planning and 3D printing in prosthetic orbital reconstruction with percutaneous implants: a technical case report 
Osseointegrated titanium implants to the cranial skeleton for retention of facial prostheses have proven to be a reliable replacement for adhesive systems. However, improper placement of the implants can jeopardize prosthetic outcomes, and long-term success of an implant-retained prosthesis. Three-dimensional (3D) computer imaging, virtual planning, and 3D printing have become accepted components of the preoperative planning and design phase of treatment. Computer-aided design and computer-assisted manufacture that employ cone-beam computed tomography data offer benefits to patient treatment by contributing to greater predictability and improved treatment efficiencies with more reliable outcomes in surgical and prosthetic reconstruction. 3D printing enables transfer of the virtual surgical plan to the operating room by fabrication of surgical guides. Previous studies have shown that accuracy improves considerably with guided implantation when compared to conventional template or freehand implant placement. This clinical case report demonstrates the use of a 3D technological pathway for preoperative virtual planning through prosthesis fabrication, utilizing 3D printing, for a patient with an acquired orbital defect that was restored with an implant-retained silicone orbital prosthesis.
PMCID: PMC5098757  PMID: 27843356
computer-assisted surgery; virtual surgical planning (VSP); 3D printing; orbital prosthetic reconstruction; craniofacial implants
9.  The Cholesterol-Lowering Effect of Alisol Acetates Based on HMG-CoA Reductase and Its Molecular Mechanism 
This study measured the impact of alisol B 23-acetate and alisol A 24-acetate, the main active ingredients of the traditional Chinese medicine Alismatis rhizoma, on total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) levels of hyperlipidemic mice. The binding of alisol B 23-acetate and alisol A 24-acetate to the key enzyme involved in the metabolism of TC, 3-hydroxy-3-methylglutary-coenzyme A (HMG-CoA) reductase, was studied using the reagent kit method and the western blotting technique combined with a molecular simulation technique. According to the results, alisol acetates significantly lower the TC, TG, and LDL-C concentrations of hyperlipidemic mice, while raising HDL-C concentrations. Alisol acetates lower HMG-CoA reductase activity in a dose-dependent fashion, both in vivo and in vitro. Neither of these alisol acetates significantly lower the protein expression of HMG-CoA. This suggests that alisol acetates lower the TC level via inhibiting the activity of HMG-CoA reductase by its prototype drug, which may exhibit an inhibition effect via directly and competitively binding to HMG-CoA. The side chain of the alisol acetate was the steering group via molecular simulation.
PMCID: PMC5107224  PMID: 27872650
10.  The Zuo Jin Wan Formula Induces Mitochondrial Apoptosis of Cisplatin-Resistant Gastric Cancer Cells via Cofilin-1 
Despite the status of cisplatin (DDP) as a classical chemotherapeutic agent in the treatment of cancer, the development of multidrug resistance often leads to a failure of DDP therapy. Here we found that phosphorylated cofilin-1 (p-cofilin-1) was overexpressed in the DDP-resistant human gastric cancer cell lines SGC7901/DDP and BGC823/DDP, relative to the respective parent cell lines (SGC7901 and BGC823), and that DDP induced the dephosphorylation of p-cofilin-1 in both parent lines but not in the DDP-resistant lines. However, we noted that the traditional Chinese medicine formula Zuo Jin Wan (ZJW) could induce the dephosphorylation of p-cofilin-1 and promote cofilin-1 translocation from the cytoplasm into the mitochondria in both SGC7901/DDP and BGC823/DDP cells. This mitochondrial translocation of cofilin-1 was found to induce the conversion of filamentous actin to globular-actin, activate mitochondrial damage and calcium overloading, and induce the mitochondrial apoptosis pathway. We further observed that these effects of ZJW on DDP-resistant human gastric cancer cell lines could be reversed via transfection with cofilin-1-specific siRNA, or treatment with a PP1 and PP2A inhibitor. These results suggest that ZJW is an effective drug therapy for patients with DDP-resistant gastric cancer.
PMCID: PMC5107242  PMID: 27872653
11.  Characterization of the Role of Hexamer AGUAAA and Poly(A) Tail in Coronavirus Polyadenylation 
PLoS ONE  2016;11(10):e0165077.
Similar to eukaryotic mRNA, the positive-strand coronavirus genome of ~30 kilobases is 5’-capped and 3’-polyadenylated. It has been demonstrated that the length of the coronaviral poly(A) tail is not static but regulated during infection; however, little is known regarding the factors involved in coronaviral polyadenylation and its regulation. Here, we show that during infection, the level of coronavirus poly(A) tail lengthening depends on the initial length upon infection and that the minimum length to initiate lengthening may lie between 5 and 9 nucleotides. By mutagenesis analysis, it was found that (i) the hexamer AGUAAA and poly(A) tail are two important elements responsible for synthesis of the coronavirus poly(A) tail and may function in concert to accomplish polyadenylation and (ii) the function of the hexamer AGUAAA in coronaviral polyadenylation is position dependent. Based on these findings, we propose a process for how the coronaviral poly(A) tail is synthesized and undergoes variation. Our results provide the first genetic evidence to gain insight into coronaviral polyadenylation.
PMCID: PMC5070815  PMID: 27760233
12.  The efficacy of semi-quantitative urine protein-to-creatinine (P/C) ratio for the detection of significant proteinuria in urine specimens in health screening settings 
SpringerPlus  2016;5(1):1791.
Urine protein detection could be underestimated using the conventional dipstick method because of variations in urine aliquots. This study aimed to assess the efficacy of the semi-quantitative urine protein-to-creatinine (P/C) ratio compared with other laboratory methods.
Random urine samples were requested from patients undergoing chronic kidney disease screening. Significant proteinuria was determined by the quantitative P/C ratio of at least 150 mg protein/g creatinine. The semi-quantitative P/C ratio, dipstick protein and quantitative protein concentrations were compared and analyzed.
In the 2932 urine aliquots, 156 (5.3 %) urine samples were considered as diluted and 60 (39.2 %) were found as significant proteinuria. The semi-quantitative P/C ratio testing had the best sensitivity (70.0 %) and specificity (95.9 %) as well as the lowest underestimation rate (0.37 %) when compared to other laboratory methods in the study. In the semi-quantitative P/C ratio test, 19 (12.2 %) had positive, 52 (33.3 %) had diluted, and 85 (54.5 %) had negative results. Of those with positive results, 7 (36.8 %) were positive detected by traditional dipstick urine protein test, and 9 (47.4 %) were positive detected by quantitative urine protein test. Additionally, of those with diluted results, 25 (48.1 %) had significant proteinuria, and all were assigned as no significant proteinuria by both tests.
The semi-quantitative urine P/C ratio is clinically applicable based on its better sensitivity and screening ability for significant proteinuria than other laboratory methods, particularly in diluted urine samples. To establish an effective strategy for CKD prevention, urine protein screening with semi-quantitative P/C ratio could be considered.
PMCID: PMC5063823  PMID: 27795933
Chronic kidney disease; Health screening; Protein-to-creatinine ratio; Proteinuria
13.  Symmetry-breaking phase transitions in highly concentrated semen 
Journal of the Royal Society Interface  2016;13(123):20160575.
New experimental evidence of self-motion of a confined active suspension is presented. Depositing fresh semen sample in an annular shaped microfluidic chip leads to a spontaneous vortex state of the fluid at sufficiently large sperm concentration. The rotation occurs unpredictably clockwise or counterclockwise and is robust and stable. Furthermore, for highly active and concentrated semen, richer dynamics can occur such as self-sustained or damped rotation oscillations. Experimental results obtained with systematic dilution provide a clear evidence of a phase transition towards collective motion associated with local alignment of spermatozoa akin to the Vicsek model. A macroscopic theory based on previously derived self-organized hydrodynamics models is adapted to this context and provides predictions consistent with the observed stationary motion.
PMCID: PMC5095218  PMID: 27733694
active fluids; self-organized hydrodynamics; Vicsek model; semen quality
14.  Coupling Mechanism of Electromagnetic Field and Thermal Stress on Drosophila melanogaster 
PLoS ONE  2016;11(9):e0162675.
Temperature is an important factor in research on the biological effects of extremely low-frequency electromagnetic field (ELF-EMF), but interactions between ELF-EMF and temperature remain unknown. The effects of ELF-EMF (50 Hz, 3 mT) on the lifespan, locomotion, heat shock response (HSR), and oxidative stress (OS) of Canton-Special (CS) and mutant w1118 flies were investigated at 25°C and 35°C (thermal stress). Results showed that thermal stress accelerated the death rates of CS and w1118 flies, shortened their lifespan, and influenced their locomotion rhythm and activity. The upregulated expression levels of heat shock protein (HSP) 22, HSP26, and HSP70 indicated that HSR was enhanced. Thermal stress-induced OS response increased malondialdehyde content, enhanced superoxide dismutase activity, and decreased reactive oxygen species level. The effects of thermal stress on the death rates, lifespan, locomotion, and HSP gene expression of flies, especially w1118 line, were also enhanced by ELF-EMF. In conclusion, thermal stress weakened the physiological function and promoted the HSR and OS of flies. ELF-EMF aggravated damages and enhanced thermal stress-induced HSP and OS response. Therefore, thermal stress and ELF-EMF elicited a synergistic effect.
PMCID: PMC5017647  PMID: 27611438
15.  Multi-epitope chimeric antigen used as a serological marker to estimate Plasmodium falciparum transmission intensity in the border area of China-Myanmar 
Following the decline of malaria transmission in many countries and regions, serological parameters have become particularly useful for estimating malaria transmission in low-intensity areas. This study evaluated a novel serological marker, Malaria Random Constructed Antigen-1 (M.RCAg-1), which contains 11 epitopes from eight Plasmodium falciparum antigens, as a tool for assessing malaria transmission intensity along the border area of China-Myanmar.
Serum from Plasmodium falciparum and P. vivax patients was used to detect the properties of M.RCAg-1 and antibody responses. Cross-sectional surveys were conducted at the China-Myanmar border and in Hainan province in 2012 and 2013 using cluster sampling. Filter blood spot papers were collected from all participants. Antibodies against M.RCAg-1 were detected using indirect ELISA. The Mann–Whitney test and Spearman’s rank correlation test were performed to analyze antibody data. P. falciparum malaria transmission intensity was estimated using a catalytic conversion model based on the maximum likelihood of generating a community seroconversion rate (SCR).
M.RCAg-1 was well-recognized by the naturally acquired anti-malaria antibodies in P. falciparum patients and had very limited cross-reactivity with P. vivax infection. The total amount of IgG antibodies was decreased with the decrease in parasitemia after taking medication and lasted several weeks. In a population survey, the antibody levels were higher in residents living close to the China-Myanmar border than those living in non-epidemic areas (P < 0.0001), but no significant difference was observed between residents from Hainan and non-epidemic areas. The calculated SCR was 0.0128 for Jieyangka, 0.004 for Susuzhai, 0.0047 for Qiushan, and 0.043 for Kayahe. The estimated exposure rate obtained from the anti-M.RCAg-1 antibody level correlated with traditional measures of transmission intensity derived from altitude.
Our study demonstrates that M.RCAg-1 is potentially useful as a serological indicator of exposure to P. falciparum malaria, especially for malaria surveillance in low transmission areas.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-016-0194-x) contains supplementary material, which is available to authorized users.
PMCID: PMC5015264  PMID: 27604628
Plasmodium falciparum; Serology; Multi-epitope chimeric antigens; Transmission intensity; China-Myanmar border
16.  Multicenter Study of Hand Carriage of Potential Pathogens by Neonatal ICU Healthcare Personnel 
A multicenter surveillance study was performed to determine the rates of hand carriage of potential pathogens among healthcare personnel in four neonatal intensive care units. Staphylococcus aureus, enterococci, and gram-negative bacilli were recovered from 8%, 3%, and 2% of 1000 hand culture samples, respectively.
PMCID: PMC4554199  PMID: 26336605
gram-negative bacilli; hand hygiene; methicillin-resistant Staphylococcus aureus (MRSA); nurses; physicians
17.  A National Multicenter Phase 2 Study of Prostate-specific Antigen (PSA) Pox Virus Vaccine with Sequential Androgen Ablation Therapy in Patients with PSA Progression: ECOG 9802 
European urology  2014;68(3):365-371.
E9802 was a phase 2 multi-institution study conducted to evaluate the safety and effectiveness of vaccinia and fowlpox prostate-specific antigen (PSA) vaccine (step 1) followed by combination with androgen ablation therapy (step 2) in patients with PSA progression without visible metastasis.
To test the hypothesis that vaccine therapy in this early disease setting will be safe and have a biochemical effect that would support future studies of immunotherapy in patients with minimal disease burden.
Design, setting, and participants
Patients had PSA progression following local therapy were treated with PROSTVAC-V (vaccinia)/TRICOM on cycle 1 followed by PROSTVAC-F (fowlpox)/TRICOM for subsequent cycles in combination with granulocyte-macrophage colony-stimulating factor (step 1). Androgen ablation was added on progression (step 2).
Outcome measurements and statistical analysis
Step 1 primary end points included progression at 6 mo and characterization of change in PSA velocity pretreatment to post-treatment. Step 2 end points included PSA response with combined vaccine and androgen ablation.
Results and limitations
In step 1, 25 of 40 eligible patients (63%) were progression free at 6 mo after registration (90% confidence interval [CI], 48–75). The median pretreatment PSA velocity was 0.13 log(PSA)/mo, in contrast to median postregistration velocity of 0.09 log(PSA)/mo (p = 0.02), which is an increase in median PSA doubling time from 5.3 mo to 7.7 mo. No grade ≥4 treatment-related toxicity was observed. In the 27 patients eligible and treated for step 2, 20 patients achieved a complete response (CR) at 7 mo (CR rate: 74%; 90% CI, 57–87). Although supportive of larger studies in the cooperative group setting, this study is limited by the small number of patients and the absence of a control group as in a phase 3 study.
A viral PSA vaccine can be administered safely in the multi-institutional cooperative group setting to patients with minimal disease volume alone and combined with androgen ablation, supporting the feasibility of future phase 3 studies in this population.
Patient summary
These data support consideration of vaccine therapy earlier in the course of prostate cancer progression with minimal disease burden in clinical practice and future studies of vaccine approaches in earlier stages of disease.
PMCID: PMC4472612  PMID: 25533418
Prostate cancer; Pox virus; Vaccine; PSA
18.  Economic burden and its associated factors of hospitalized patients infected with A (H7N9) virus: a retrospective study in Eastern China, 2013–2014 
H7N9 continues to cause human infections and remains a pandemic concern. Understanding the economic impacts of this novel disease is important for making decisions on health resource allocation, including infectious disease prevention and control investment. However, there are limited data on such impacts.
Hospitalized laboratory-confirmed H7N9 patients or their families in Jiangsu Province of China were interviewed. Patients’ direct medical costs of hospitalization were derived from their hospital bills. A generalized linear model was employed to estimate the mean direct medical costs of patients with different characteristics.
The mean direct cost of hospitalization for H7N9 was estimated to be ¥ 71 060 (95 % CI, 48 180–104 820), i.e., US$ 10 996 (95 % CI, 7 455–16 220), and was ¥12 060 (US$ 1 861), ¥136 120 (US$ 21 001) and ¥218 610 (US$ 33 728) for those who had mild or severe symptoms or who died, respectively. The principal components of the total fees differed among patients with different disease severity, although medication fees were always the largest contributors. Disease severity, proportion of reimbursement and family member monthly average income were identified as the key factors that contributed to a patient’s direct medical cost of hospitalization.
The direct medical costs of hospitalized patients with H7N9 are significant, and far surpass the annual per capita income of Jiangsu Province, China. The influencing factors identified should be taken into account when developing related health insurance policies and making health resource allocation.
Trial registration
Not applicable. This is a survey study with no health care intervention implemented on human participants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-016-0170-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5007809  PMID: 27580946
H7N9; Avian influenza; Human infections; Direct medical costs; Hospitalization
19.  Lymphocyte‐activation gene‐3, an important immune checkpoint in cancer 
Cancer Science  2016;107(9):1193-1197.
Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen‐4 (CTLA‐4), programmed cell death ligand‐1 (PD‐L1) and programmed cell death‐1 (PD‐1). Immunotherapy targeting the PD‐1/PD‐L1 checkpoints has shown promising efficacy in non‐small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte‐activation gene‐3 (LAG‐3) is another vital checkpoint that may have a synergistic interaction with PD‐1/PD‐L1. Here we review the LAG‐3 function in cancer, clinical trials with agents targeting LAG‐3 and the correlation of LAG‐3 with other checkpoints.
PMCID: PMC5021038  PMID: 27297395
Cancer checkpoints; clinical trial; immunotherapy; lymphocyte‐activation gene‐3; soluble LAG‐3
20.  Increased Serum Levels of Anti-Carbamylated 78-kDa Glucose-Regulated Protein Antibody in Patients with Rheumatoid Arthritis 
The objective of this study was to investigate the presence and titer of anti-carbamylated 78-kDa glucose-regulated protein (anti-CarGRP78) antibody in serum from controls, and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren syndrome (pSS). Thirty-three RA patients, 20 SLE patients, 20 pSS patients, and 20 controls were enrolled from our outpatient clinic. GRP78 was cloned and carbamylated. Serum titers of anti- cyclic citrullinated peptides (anti-CCP), anti-GRP78, and anti-CarGRP78 were measured with an enzyme-linked immunosorbent assay. No differences in serum titers of anti-GRP78 antibody in patients with RA, SLE, or pSS compared with the controls were observed. Serum levels of anti-carGRP78 antibody in patients with RA, but not SLE or pSS, were significantly higher compared with the controls (OD405 0.15 ± 0.08 versus 0.11 ± 0.03, p = 0.033). There was a positive correlation between the serum levels of anti-GRP78 antibody, but not anti-CarGRP78 antibody, with the levels of anti-CCP antibody in patients with RA. Both anti-GRP78 and anti-carGRP78 antibodies failed to correlate with C-reactive protein levels in patients with RA. In conclusion, we demonstrated the presence of anti-CarGRP78 antibody in patients with RA. In addition, the serum titer of anti-CarGRP78 antibody was significantly elevated in patients with RA compared with the controls. Anti-CarGRP78 antibody could also be detected in patients with SLE or pSS.
PMCID: PMC5037787  PMID: 27618024
GRP78; autoantibodies; rheumatoid arthritis; systemic autoimmune diseases
21.  Comparison of the PEEK cage and an autologous cage made from the lumbar spinous process and laminae in posterior lumbar interbody fusion 
A prospective cohort study was performed to evaluate the clinical and radiological outcomes following posterior lumbar interbody fusion (PLIF) in patients treated with a PEEK cage compared to those treated with an autologous cage using the lumbar spinous process and laminae (ACSP).
Sixty-nine consecutive patients with lumbar degenerative disc disease were randomly assigned to either a PEEK cage (group A, n = 34) or an ACSP (group B, n = 35). Monosegmental PLIF was performed in all patients. Mean lumbar lordosis, mean disc height, visual analog scale (VAS) scores, functional outcomes, fusion rates and complication rates were recorded and compared. The patients were followed postoperatively for a minimum of 2 years.
Successful radiographic fusion was documented in all patients. No flexion–extension hypermobility or pedicle screw loosening or breakage occurred during the follow-up period. No significant difference existed between the 2 groups when comparing the mean lumbar lordosis, mean disc height, visual analog scale (VAS) scores, functional outcomes, fusion rates or complication rates. Overall satisfactory results were achieved in both groups.
The results suggest that the ACSP appears to be equally as safe and effective as the PEEK cage.
Trial registration
ISRCTN25558534. Retrospectively registered 16/02/2016.
PMCID: PMC5004315  PMID: 27577978
Posterior lumbar interbody fusion (PLIF); PEEK cage; Spinous process; Lumbar degenerative disease
22.  Comparison of Autonomic Reactions during Urodynamic Examination in Patients with Spinal Cord Injuries and Able-Bodied Subjects 
PLoS ONE  2016;11(8):e0161976.
This study compares heart rate variability (HRV) and systolic blood pressure (SBP) changes of spinal cord injury (SCI) patients during urodynamic study (UDS) with able-bodied controls.
Twenty four complete suprasacral SCI patients (12 tetraplegia and 12 paraplegia) and 12 age-matched able-bodied volunteers received BP and HRV evaluation throughout urodynamic examination. We chose seven time points during the examinations: resting, Foley catheter insertion, start of infusion, and infused volume reaching 1/4, 2/4, 3/4 and 4/4 of maximal capacity. At each time point, electrocardiogram with a duration of 5 min was used for power spectral density analysis of HRV.
Only control subjects displayed significant elevation of SBP during Foley catheter insertion compared to resting values. Both control and tetraplegic groups experienced significant elevation of SBP at maximal bladder capacity compared to resting values. Tetraplegic values were also significantly greater than the other two groups. Control subjects displayed significant elevation of low frequency/high frequency (LF/HF) ratios during Foley catheter insertion and when approaching maximum bladder capacity. These findings were not seen in the paraplegic and tetraplegic groups. However, subgroup analysis of tetraplegic subjects with SBP elevation >50 mmHg demonstrated a similar LF/HF response to the able-bodied controls.
Tetraplegic patients experienced BP elevation but did not experience significant changes in HRV during bladder distension. This finding may imply that different neurological pathways contribute to AD reaction and HRV changes during bladder distension. However, profound AD during UDS in tetraplegic patients was associated with corresponding changes in HRV. Whether HRV monitoring would be beneficial in SCI patients presenting with significant AD, it needs further studies to elucidate.
PMCID: PMC5004842  PMID: 27575616
23.  15-Lipoxygenase-1 Is Involved in the Effects of Atorvastatin on Endothelial Dysfunction 
Mediators of Inflammation  2016;2016:6769032.
Statins exert pleiotropic effects on endothelial cells in addition to lowering cholesterol. 15-Lipoxygenase-1 (ALOX15) has been implicated in vascular inflammation and disease. The relationship between atorvastatin and ALOX15 was investigated using a rat carotid artery balloon-injury model. Hematoxylin and eosin (HE) staining showed that ALOX15 overexpression increased the thickness of the intima-media (IMT). Immunohistochemistry and western blotting showed that atorvastatin increased the expression of cellular adhesion molecules (CAMs) but decreased the expression of endothelial nitric oxide synthase (eNOS); these effects of atorvastatin were blocked by ALOX15 overexpression. In human umbilical venous endothelial cells (HUVECs), silencing of ALOX15 enhanced the effects of atorvastatin on endothelial function. Expression levels of CAMs and Akt/eNOS/NO under oxidized low-density lipoprotein (ox-LDL) stimulation were modulated by ALOX15 inhibitor and ALOX15 small interfering RNA (siRNA). Atorvastatin abolished the activation of nuclear factor-kappa B (NF-κB) induced by ox-LDL. Exposure to ox-LDL induced upregulation of ALOX15 in HUVECs, but this effect was partially abolished by atorvastatin or the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). These results demonstrate that regulation of ALOX15 expression might be involved in the effects of atorvastatin on endothelial dysfunction.
PMCID: PMC4995339  PMID: 27594770
24.  EW_dmGWAS: edge-weighted dense module search for genome-wide association studies and gene expression profiles 
Bioinformatics  2015;31(15):2591-2594.
Summary: We previously developed dmGWAS to search for dense modules in a human protein–protein interaction (PPI) network; it has since become a popular tool for network-assisted analysis of genome-wide association studies (GWAS). dmGWAS weights nodes by using GWAS signals. Here, we introduce an upgraded algorithm, EW_dmGWAS, to boost GWAS signals in a node- and edge-weighted PPI network. In EW_dmGWAS, we utilize condition-specific gene expression profiles for edge weights. Specifically, differential gene co-expression is used to infer the edge weights. We applied EW_dmGWAS to two diseases and compared it with other relevant methods. The results suggest that EW_dmGWAS is more powerful in detecting disease-associated signals.
Availability and implementation: The algorithm of EW_dmGWAS is implemented in the R package dmGWAS_3.0 and is available at
Contact: or
Supplementary information: Supplementary materials are available at Bioinformatics online.
PMCID: PMC4514922  PMID: 25805723
25.  Sulforaphane protects against acrolein-induced oxidative stress and inflammatory responses: modulation of Nrf-2 and COX-2 expression 
Archives of Medical Science : AMS  2016;12(4):871-880.
Acrolein (2-propenal) is a reactive α, β-unsaturated aldehyde which causes a health hazard to humans. The present study focused on determining the protection offered by sulforaphane against acrolein-induced damage in peripheral blood mononuclear cells (PBMC).
Material and methods
Acrolein-induced oxidative stress was determined through evaluating the levels of reactive oxygen species, protein carbonyl and sulfhydryl content, thiobarbituric acid reactive species, total oxidant status and antioxidant status (total antioxidant capacity, glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity). Also, Nrf-2 expression levels were determined using western blot analysis. Acrolein-induced inflammation was determined through analyzing expression of cyclooxygenase-2 by western blot and PGE2 levels by ELISA. The protection offered by sulforaphane against acrolein-induced oxidative stress and inflammation was studied.
Acrolein showed a significant (p < 0.001) increase in the levels of oxidative stress parameters and down-regulated Nrf-2 expression. Acrolein-induced inflammation was observed through upregulation (p < 0.001) of COX-2 and PGE2 levels. Pretreatment with sulforaphane enhanced the antioxidant status through upregulating Nrf-2 expression (p < 0.001) in PBMC. Acrolein-induced inflammation was significantly inhibited through suppression of COX-2 (p < 0.001) and PGE2 levels (p < 0.001).
The present study provides clear evidence that pre-treatment with sulforaphane completely restored the antioxidant status and prevented inflammatory responses mediated by acrolein. Thus the protection offered by sulforaphane against acrolein-induced damage in PBMC is attributed to its anti-oxidant and anti-inflammatory potential.
PMCID: PMC4947616  PMID: 27478470
oxidative stress; acrolein; sulforaphane; inflammation

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