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1.  A study of suicidal ideation in acute ischemic stroke patients 
Background
Increasing evidences indicate that stroke confers a substantial risk for suicidal ideation. The aim of this study was to identify risk factors of suicidal ideation in acute ischemic stroke patients.
Method
A total of 271 consecutive patients with acute ischemic stroke were recruited in Huai-He hospital or the First People’s Hospital, Kaifeng City, China. Demographic and clinical variables were collected and evaluated. Suicidal ideation was assessed using the Beck Scale for Suicide Ideation (BSI). Multivariate logistic regression was applied to determine the risk factors of suicidal ideation.
Results
Suicidal ideation was identified in 29 patients (10.7%). It was more frequent in patients who lived in rural region, with pre-/post-stroke depression or diabetes, had a higher NIHSS score, had no confidence in disease treatment, or had a poor coping style. Living in rural region (OR 2.59, 95% CI 1.02-6.58), the presence of pre-stroke depression (OR 11.74, 95% CI 4.45-31.01), stroke severity (OR 1.20, 95% CI 1.08-1.33), having no confidence in disease treatment (OR 14.70, 95% CI 2.60-83.15), and post-stroke depression (OR 16.22, 95% CI 6.40-41.10) were independent risk factors of suicidal ideation.
Conclusion
Several factors may be associated with an increased risk of suicidal ideation in acute ischemic stroke patients, including pre-/post-stroke depression, more severe stroke, having no confidence in treatment, as well as living in rural region. Our findings may have implication in risk assessment and intervention for acute ischemic stroke patients in reducing the burdens of suicidal ideation.
doi:10.1186/s12955-014-0198-9
PMCID: PMC4308882  PMID: 25613218
Ischemic stroke; Suicidal ideation; Depression; Risk factor
2.  Autoantibodies in Chinese patients with chronic hepatitis B: Prevalence and clinical associations 
AIM: To investigate the prevalence of autoantibodies and their associations with clinical features in Chinese patients with chronic hepatitis B (CHB).
METHODS: A total of 325 Chinese patients with CHB were enrolled in this retrospective, hospital-based study. Patients with chronic hepatitis C (CHC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC) were included, with healthy donors acting as controls. A panel of autoantibodies that serologically define AIH and PBC was tested by indirect immunofluorescence assay and line immunoassay. The AIH-related autoantibody profile included homogeneous anti-nuclear antibodies (ANA-H), smooth-muscle antibodies, anti-liver kidney microsome type 1, anti-liver cytosolic antigen type 1, and anti-soluble liver antigen/liver pancreas; the PBC-related antibodies were characterized by ANA-nuclear dots/membranous rim-like, anti-mitochondrial antibodies-M2 (AMA-M2), anti-BPO (recombinant antigen targeted by AMA-M2), anti-Sp100, anti-promyelocytic leukemia protein (anti-PML), and anti-gp210. The dichotomization of clustering was used to unequivocally designate the AIH or PBC profiles for each case. Anti-Ro52 antibodies were also tested.
RESULTS: The prevalence of any autoantibody in CHB amounted to 58.2%, which was similar to the 66.2% prevalence in CHC, significantly higher than the 6.7% in the healthy controls (P < 0.001), and lower than the 100% found in AIH and PBC (P = 0.004 and P < 0.001, respectively). There were more anti-PML and anti-gp210 antibodies among the CHB patients than the CHC patients (11.1% vs 0%, P = 0.003; 12.6% vs 0%, P < 0.001, respectively). The prevalence and titer of AMA, anti-BPO, anti-PML, and anti-gp210 were higher in PBC than in those with CHB. Among the CHB patients, the prevalence of ANA, especially ANA-H, was significantly lower in patients with compensated and decompensated cirrhosis compared with patients without cirrhosis. Thirty-eight cases of hepatocellular carcinoma (HCC) in CHB showed a significant difference compared with non-HCC patients in the prevalence of anti-PML (0% vs 12.5%, P = 0.013). Dichotomization of the autoantibodies revealed that the PBC profile was more prevalent in patients with CHB than in those with CHC, and that it was strongly correlated with both compensated and decompensated cirrhosis. In contrast, the prevalence of the AIH profile was significantly higher in non-cirrhosis patients with CHB than in those with compensated cirrhosis (18.5% vs 8.2%, P = 0.039). Moreover, the AIH profile was also closely associated with hepatitis B e-antigen positivity.
CONCLUSION: ANA-H could be an indicator of early-stage CHB. Dichotomizing the autoantibody profiles revealed that the PBC profile is strongly associated with cirrhosis in CHB.
doi:10.3748/wjg.v21.i1.283
PMCID: PMC4284347  PMID: 25574103
Autoantibodies; Chronic hepatitis B; Autoimmune hepatitis; Primary biliary cirrhosis; Cirrhosis; Hepatocellular carcinoma
3.  The association of prevalent kidney stone disease with mortality in U.S. adults: the National Health and Nutrition Examination Survey III, 1988–1994 
American journal of nephrology  2013;37(5):501-506.
Background
Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear.
Methods
We used The Third National Health and Nutrition Examination Survey, a large US population-based study with mortality data through 2006 determined via linkage to the National Death Index to examine kidney stone disease in relation to all-cause and CV mortality risks.
Results
Among 14,879 men and women over 18 years of age who were eligible for analysis, 683 participants reported a history of kidney stones. There was a total of 3,590 all-cause and 1,608 CV deaths occurred during a median follow up of 14.9 years. Stone formers had a significantly higher risk for all-cause mortality (HR 1.95, 95% CI 1.64–2.33, p<0.0001), and CV mortality (HR 2.05, 95% CI 1.60–2.62, p<0.0001) in unadjusted analyses. However, after multivariate adjustment for age, gender, race and poverty, stone formers no longer had increased risk for all-cause mortality (HR 1.08, 95% CI 0.93–1.26, p=0.3) and CV mortality (HR 1.07, 95% CI 0.84–1.36, p=0.6). Results remain unchanged after further adjustment for other clinical variables including history of hypertension, diabetes, and CV disease.
Conclusion
The increased risk of all-cause and CV mortality in kidney stone formers is likely a reflection of unique demographics and associated co-morbidities. There is no independent association of prevalent kidney stone disease with all-cause and CV mortality.
doi:10.1159/000350691
PMCID: PMC4278430  PMID: 23635714
Mortality; Cardiovascular disease; Kidney stone disease
4.  The Reduction of Regional Cerebral Blood Flow in Normal-Appearing White Matter Is Associated with the Severity of White Matter Lesions in Elderly: A Xeon-CT Study 
PLoS ONE  2014;9(11):e112832.
White matter lesions (WMLs) in normal elderly are related to chronic ischemia, and progression of WML occurs mostly in moderate to severe disease. However, the mechanism is uncertain. Thus, we enrolled fifty-six normal elderly patients without large artery disease. The severity of WML on MRI was graded as grade 0, I, II and III using the modified Fazekas scale. Cerebral blood flow (CBF) was measured by Xenon-CT. We found that CBF (mL/100 g/min) within periventricular lesions and in the right and left centrum semiovales were 20.33, 21.27 and 21.03, respectively, in group I; 16.33, 15.55 and 15.91, respectively, in group II; and 14.05, 14.46 and 14.23, respectively, in group III. CBF of normal-appearing white matter (NAWM) around periventricular areas and in the right and left centrum semiovales were 20.79, 22.26 and 22.15, respectively, in group 0; 21.12, 22.17 and 22.25, respectively, in group I; 18.02, 19.45 and 19.62, respectively, in group II; and 16.38, 18.18 and 16.74, respectively, in group III. Significant reductions in CBF were observed not only within lesions but also in NAWM surrounding the lesions. In addition, CBF was reduced significantly within lesions compared to NAWM of the same grade. Furthermore, CBF was reduced significantly in NAWM in grades II and III when compared to grades 0 and I. Our finding indicates that ischemia may play a role in the pathogenesis of WML. Additionally, our finding provides an alternative explanation for finding that the progression of WML occurred more commonly in patients with moderate to severe WML.
doi:10.1371/journal.pone.0112832
PMCID: PMC4234500  PMID: 25401786
5.  Evaluating the Individualized Treatment of Traditional Chinese Medicine: A Pilot Study of N-of-1 Trials 
Purpose. To compare the efficacy of individualized herbal decoction with controlled decoction for individual patients with stable bronchiectasis. Methods. We conducted N-of-1 RCTs (single-patient, double-blind, randomized, multiple crossover design) in 3 patients with stable bronchiectasis. The primary outcome was patient self-rated symptom scores on visual analogue scales. Secondary outcome was 24-hour sputum volume. A clinical efficacy criterion which combined symptoms score and medication preference was also formulated. Results. All three patients showed various degrees of improvement on their symptoms and one patient's (Case 3) 24 h sputum volume decreased from 70 mL to 30 mL. However, no significant differences were found between individualized herbal decoction and control decoction on symptoms score, or on 24-hour sputum volume. One patient (Case 2) had clear preference for the individualized herbal decoction over the standard one with the confirmation after unblinding. We therefore considered this case as clinically important. Discussion. N-of-1 trials comply with individualized philosophy of TCM clinical practice and had good compliance. It is necessary to set up clinical efficacy criteria and to consider the interference of acute exacerbation.
doi:10.1155/2014/148730
PMCID: PMC4244929  PMID: 25477988
6.  Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy-related positive feedback loops signaling 
Background
MUC4 plays important roles in the malignant progression of human pancreatic cancer. But the huge length of MUC4 gene fragment restricts its functional and mechanism research. As one of its splice variants, MUC4/Y with coding sequence is most similar to that of the full-length MUC4 (FL-MUC4), together with alternative splicing of the MUC4 transcript has been observed in pancreatic carcinomas but not in normal pancreas. So we speculated that MUC4/Y might be involved in malignant progression similarly to FL-MUC4, and as a research model of MUC4 in pancreatic cancer. The conjecture was confirmed in the present study.
Methods
MUC4/Y expression was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) using gene-specific probe in the clinic samples. The effects of MUC4/Y were observed by serial in vitro and in vivo experiments based on stable over-expressed cell model. The underlying mechanisms were investigated by sequence-based transcriptome analysis and verified by qRT-PCR, Western blot and enzyme-linked immunosorbent assays.
Results
The detection of clinical samples indicates that MUC4/Y is significantly positive-correlated with tumor invasion and distant metastases. Based on stable forced-expressed pancreatic cancer PANC-1 cell model, functional studies show that MUC4/Y enhances malignant activity in vitro and in vivo, including proliferation under low-nutritional-pressure, resistance to apoptosis, motility, invasiveness, angiogenesis, and distant metastasis. Mechanism studies indicate the novel finding that MUC4/Y triggers malignancy-related positive feedback loops for concomitantly up-regulating the expression of survival factors to resist adverse microenvironment and increasing the expression of an array of cytokines and adhesion molecules to affect the tumor milieu.
Conclusions
In light of the enormity of the potential regulatory circuitry in cancer afforded by MUC4 and/or MUC4/Y, repressing MUC4 transcription, inhibiting post-transcriptional regulation, including alternative splicing, or blocking various pathways simultaneously may be helpful for controlling malignant progression. MUC4/Y- expression model is proven to a valuable tool for the further dissection of MUC4-mediated functions and mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0309-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0309-8
PMCID: PMC4236435  PMID: 25367394
MUC4/Y; Alternative splicing; Pancreatic neoplasms; Cell movement; Angiogenesis; Neoplasm metastasis; Gene expression regulation; Signal transduction
7.  Ultrasound Imaging in the Diagnosis of Benign and Suspicious Adrenal Lesions 
Background
The purpose of this study was to define the ultrasound imaging characteristics of adrenal tumors and to assess the performance of ultrasound in differentiating benign ‘leave-alone’ lesions from suspicious lesions.
Material/Methods
We enrolled 882 patients in this study. The nature of each lesion was determined by histopathology. Ultrasound finding of each lesion was compared with its corresponding histopathologic result. The final study group consisted of 911 adrenal masses in 882 patients. All images were reviewed by 2 experienced investigators in a double blind manner.
Results
There were 553 adenomas identified in the study, which constituted 60.70% of the lesions. There were 161 pheochromocytomas (17.67%), 49 myelolipomas (5.38%), 39 cysts (4.28%), 37 metastasis (4.06%), 35 ganglioneuromas (3.84%), 22 lymphomas (2.41%), and 15 cortical carcinomas (1.65%). The sensitivity, specificity, and accuracy of ultrasound-based diagnosis were 89%, 99%, and 93.9%, respectively. A positive predictive value of 90.9% and a negative predictive value of 94.2% were obtained in this study.
Conclusions
This large-sample study showed that ultrasound was a reliable method in differentiating benign ‘leave-alone’ lesions from suspicious lesions.
doi:10.12659/MSM.890800
PMCID: PMC4228948  PMID: 25363391
Adrenal Medulla; Pharmacy; Ultrasonography
8.  Diabetes, Prediabetes and the Survival of Nasopharyngeal Carcinoma: A Study of 5,860 Patients 
PLoS ONE  2014;9(10):e111073.
Background
The incidence of diabetes is increasing. But the impact of diabetes and prediabetes on survival of patients with nasopharyngeal carcinoma (NPC) has received little evaluation.
Methods
In a cohort of 5,860 patients, we compared the disease specific survival (DSS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) of patients with diabetes, prediabetes and normoglycemia defined by pretreatment fasting plasma glucose (FPG) using Kaplan–Meier method, log-rank test and Cox proportional hazards model.
Results
Comparing to normoglycemic patients, the diabetic and the prediabetic were generally older, fatter, had hypertension, heart diseases and hyperlipaemia and usually received radiotherapy alone. But both the diabetic and the prediabetic had similar DSS, LRFS and DMFS to normoglycemic patients, even adjusting for such important factors as age, gender, smoking, drinking, hypertension, heart diseases, body mass index, hyperlipaemia, titer of VCA-IgA and EA-IgA, pathology, T-stage, N-stage, chemotherapy and radiotherapy (P>0.05 for all). Additionally, the findings remained unchanged in sensitivity analysis by excluding patients with known diabetes history and in subgroups of the various factors.
Conclusions
The diabetic and prediabetic NPC patients had similar survival to normoglycemic NPC patients. These data, in the largest reported cohort, are the first to evaluate the association between diabetes, prediabetes and the survival in NPC. The findings are relevant to patient management and provided evidence of the effect on this disease exerted by comorbidities.
doi:10.1371/journal.pone.0111073
PMCID: PMC4211733  PMID: 25350747
9.  Characterization of argon direct-current glow discharge with a longitudinal electric field applied at ambient air 
Scientific Reports  2014;4:6323.
A direct-current-driven plasma jet is developed by applying a longitudinal electric field on the flowing argon at ambient air. This plasma shows a torch shape with its cross-section increased from the anode to the cathode. Comparison with its counterparts indicates that the gas flow plays a key role in variation of the plasma structure and contributes much to enlarging the plasma volume. It is also found that the circular hollow metal base promotes generation of plasma with a high-power volume density in a limited space. The optical emission spectroscopy (OES) diagnosis indicates that the plasma comprises many reactive species, such as OH, O, excited N2, and Ar metastables. Examination of the rotational and vibrational temperature indicates that the plasma is under nonequilibrium condition and the excited species OH(A 2Σ+), O(5P), and N2(C 3Πu) are partly generated by energy transfer from argon metastables. The spatially resolved OES of plasma reveals that the negative glow, Faraday dark space, and positive column are distributed across the gas gap. The absence of the anode glow is attributed to the fact that many electrons in the vicinity of the anode follow ions into the positive column due to the ambipolar diffusion in the flowing gas.
doi:10.1038/srep06323
PMCID: PMC4159630  PMID: 25205176
10.  Efficacy and safety of immunosuppressive therapy in the treatment of seronegative hepatitis associated aplastic anemia 
Objective
To investigate the clinical characteristics of seronegative hepatitis-associated aplastic anemia (AA) (SNHAA) and hepatitis B virus (HBV) infection complicating AA (HBVAA), and thereby compare the efficacy of immunosuppressive therapy (IST).
Methods
An analysis was conducted on the clinical data of ten patients with SNHAA out of 332 cases of AA from our center at AA diagnosis, and on the efficacy of IST. This was compared to 22 cases of HBVAA at AA onset as well as the associated IST outcomes.
Results
Nine patients with SNHAA developed severe aplastic anemia, with a median age of 18 years. After IST, six (60%) of the SNHAA patients achieved complete remission and two achieved partial remission. The patients with HBVAA had a total response rate of 82.3%. The disease recurred in two HBVAA patients. No statistically significant differences were observed in response rate, mortality, and recurrence rate between both groups. As compared with HBVAA, patients with SNHAA had a shorter interval from the acute episode of hepatitis to AA onset (4 months versus 92 months, P=0.00), a quicker response to IST (2.5 months versus 4.5 months, P=0.018), a lower proportion of bone marrow hematopoietic tissues (20.6% versus 23.6%, P=0.03), and lower white blood cell and absolute neutrophil count (0.8×109/L versus 1.23×109/L and 0.26×109/L versus 0.58×109/L, P=0.026 and P=0.0009, respectively). No significant liver damage or hepatitis B fulminant infection was observed in either group during the follow-up.
Conclusion
The prevalence of SNHAA is 3.01%. SNHAA often presents as severe AA and responds to IST quickly. Neither hepatitis prior to AA nor AA complicating HBV infection have been shown to influence the early efficacy of IST and adverse events, and HBV may not be the causative agent of AA.
doi:10.2147/DDDT.S67908
PMCID: PMC4166905  PMID: 25246771
hepatitis-associated aplastic anemia; hepatitis B infection; liver injury
11.  Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof of principle study with colorectal cancer 
Oncogene  2013;33(7):814-822.
Herein we report a proof of principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human- and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A, and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.
doi:10.1038/onc.2013.17
PMCID: PMC3932186  PMID: 23416983
CRC driver-passenger distinction; sporadic canine CRCs; human-dog comparison; epithelial cell apicobasal polarity; genomic amplifications/deletions
12.  A Critical Role for ZDHHC2 in Metastasis and Recurrence in Human Hepatocellular Carcinoma 
BioMed Research International  2014;2014:832712.
It has been demonstrated that loss of heterozygosity (LOH) was frequently observed on chromosomes 8p22-p23 in hepatocellular carcinoma (HCC) and was associated with metastasis and prognosis of HCC. However, putative genes functioning on this chromosomal region remain unknown. In this study, we evaluated LOH status of four genes on 8p22-p23 (MCPH1, TUSC3, KIAA1456, and ZDHHC2). LOH on ZDHHC2 was associated with early metastatic recurrence of HCC following liver transplantation and was correlated with tumor size and portal vein tumor thrombi. Furthermore, our results indicate that ZDHHC2 expression was frequently decreased in HCC. Overexpression of ZDHHC2 could inhibit proliferation, migration, and invasion of HCC cell line Bel-7402 in vitro. These results suggest an important role for ZDHHC2 as a tumor suppressor in metastasis and recurrence of HCC.
doi:10.1155/2014/832712
PMCID: PMC4068081  PMID: 24995331
13.  Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism 
Molecular Cancer  2014;13:130.
Background
Increasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified.
Methods
In this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software.
Results
We found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.
Conclusions
The present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.
doi:10.1186/1476-4598-13-130
PMCID: PMC4047260  PMID: 24884523
Yin Yang-1; Pancreatic ductal adenocarcinoma; Metastasis; MMP10; MUC4; MEF2C
14.  Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer 
BMC Cancer  2014;14:290.
Background
The efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non–small-cell lung cancer (NSCLC).
Methods
Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS).
Results
Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%).
Conclusion
Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.
Trial registration
ClinicalTrials.gov: NCT00768755 (October 7, 2008).
doi:10.1186/1471-2407-14-290
PMCID: PMC4017965  PMID: 24766732
Axitinib; Pemetrexed; Cisplatin; Non-squamous; NSCLC
15.  Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses 
Vaccine  2013;31(15):1898-1904.
Epitopes of the circumsporozoite (CS) protein of Plasmodium falciparum, the most pathogenic species of the malaria parasite, have been shown to elicit protective immunity in experimental animals and human volunteers. The mechanisms of immunity include parasite-neutralizing antibodies that can inhibit parasite motility in the skin at the site of infection and in the bloodstream during transit to the hepatocyte host cell and also block interaction with host cell receptors on hepatocytes. In addition, specific CD4+ and CD8+ cellular mechanisms target the intracellular hepatic forms, thus preventing release of erythrocytic stage parasites from the infected hepatocyte and the ensuing blood stage cycle responsible for clinical disease. An innovative method for producing particle vaccines, layer-by-layer (LbL) fabrication of polypeptide films on solid CaCO3 cores, was used to produce synthetic malaria vaccines containing a tri-epitope CS peptide T1BT* comprising the antibody epitope of the CS repeat region (B) and two T-cell epitopes, the highly conserved T1 epitope and the universal epitope T*. Mice immunized with microparticles loaded with T1BT* peptide developed parasite-neutralizing antibodies and malaria-specific T-cell responses including cytotoxic effector T-cells. Protection from liver stage infection following challenge with live sporozoites from infected mosquitoes correlated with neutralizing antibody levels. Although some immunized mice with low or undetectable neutralizing antibodies were also protected, depletion of T-cells prior to challenge resulted in the majority of mice remaining resistant to challenge. In addition, mice immunized with microparticles bearing only T-cell epitopes were not protected, demonstrating that cellular immunity alone was not sufficient for protective immunity. Although the microparticles without adjuvant were immunogenic and protective, a simple modification with the lipopeptide TLR2 agonist Pam3Cys increased the potency and efficacy of the LbL vaccine candidate. This study demonstrates the potential of LbL particles as promising malaria vaccine candidates using the T1BT* epitopes from the P. falciparum CS protein.
doi:10.1016/j.vaccine.2013.02.027
PMCID: PMC3611586  PMID: 23481177
malaria vaccines; microparticle; peptide; sporozoite
16.  Role of Interleukin-22 in liver diseases 
Inflammation Research  2014;63(7):519-525.
Introduction
Interleukin (IL)-22, originally referred to as IL-TIF for IL-10-related T cell-derived inducible factor, is a member of the IL-10-like cytokine family. IL-22 is highly expressed by Th17 cells and is tightly linked to chronic inflammation, including inflammatory bowel disease and local intestinal inflammation among others.
Materials and methods
A PubMed and Web of Science databases search was performed for studies providing evidences on the role of IL-22 in liver diseases.
Conclusion
IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22 receptor 1 and IL-10 receptor 2. This review concisely summarizes the role of IL-22 in the development progression of liver disease of different etiologies. It is focused mainly on the IL-22 intracellular signaling and its influence on liver diseases.
doi:10.1007/s00011-014-0727-3
PMCID: PMC4050291  PMID: 24623532
IL-22; Liver disease; Therapeutic
18.  Tissue elasticity displayed by elastography and its correlation with the characteristics of collagen type I and type III in prostatic stroma 
Asian Journal of Andrology  2014;16(2):305-308.
We investigated the prostate elasticity displayed by elastography and its correlation with the content and distribution of collagen type I (Col1) and type III (Col3). A total of 62 patients underwent transrectal real-time tissue elastography (TRTE) examinations. Targeted biopsies were performed after 12-core systematic biopsy. The tissues corresponding to the elastograms were stained with picric acid-sirius red. The distribution of Col1 and type Col3 was observed, and the collagen volume fraction (CVF) of these two types of collagen fibers was calculated. The CVFs of Col1 in the stiff and soft groups were 0.05 ± 0.02 and 0.02 ± 0.01 (P = 0.002), respectively. The CVFs of Col3 in the stiff and soft groups were 0.05 ± 0.04 and 0.07 ± 0.03 (P = 0.13), respectively. The circular analysis results showed that collagen fibers were disorganized both in the soft and stiff groups. Col1 and Col3 were mainly cross-linked, and some parallelization was observed in the sections. The distributions of Col1 and Col3 were different between the stiff and soft groups (P = 0.03). In conclusion, the texture of the prostate is due to the content of Col1 and its relative correlation with Col3.
doi:10.4103/1008-682X.122582
PMCID: PMC3955345  PMID: 24435054
elastography; extracellular matrix; lesion; prostate; ultrasound
19.  IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis 
Purpose.
We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes.
Methods.
To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α.
Results.
Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active.
Conclusions.
Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
IGFBP-3 KO mice have the early characteristics of diabetic retinopathy noted in rodents.
doi:10.1167/iovs.13-12497
PMCID: PMC3741024  PMID: 23868984
IGFBP-3; apoptosis; TNF-α
20.  Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions 
Background
To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features.
Methods
Between July 2005 and July 2012, 4,453 ultrasound-detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features.
Results
Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter ≤10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01).
Conclusions
Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm.
doi:10.1186/1477-7819-12-7
PMCID: PMC3895748  PMID: 24400744
Breast; Beast cancer; Core needle biopsy; Surgical excision; Ultrasound
21.  Complete Genome Sequence of Exiguobacterium sp. Strain MH3, Isolated from Rhizosphere of Lemna minor 
Genome Announcements  2013;1(6):e01059-13.
We report the complete genome sequence of Exiguobacterium sp. strain MH3, isolated from the rhizosphere of duckweed. The genome assembly is 3.16 Mb, with a G+C content of 47.24%, and it may provide useful information about plant-microbe interactions and the genetic basis for the tolerance of the strain to various environmental stresses.
doi:10.1128/genomeA.01059-13
PMCID: PMC3868855  PMID: 24356831
22.  DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells 
Cell stem cell  2011;8(6):10.1016/j.stem.2011.04.004.
Summary
DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes up-regulated following deletion of the H3K9 methyltransferase Setdb1 are distinct from those de-repressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly de-repressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of up-regulated genes are induced in association with de-repression of promoter proximal ERVs, half in the context of “chimaeric” transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs.
doi:10.1016/j.stem.2011.04.004
PMCID: PMC3857791  PMID: 21624812 CAMSID: cams3765
23.  Cell-Cycle Control of Developmentally Regulated Transcription Factors Accounts for Heterogeneity in Human Pluripotent Cells 
Stem Cell Reports  2013;1(6):532-544.
Summary
Heterogeneity within pluripotent stem cell (PSC) populations is indicative of dynamic changes that occur when cells drift between different states. Although the role of metastability in PSCs is unclear, it appears to reflect heterogeneity in cell signaling. Using the Fucci cell-cycle indicator system, we show that elevated expression of developmental regulators in G1 is a major determinant of heterogeneity in human embryonic stem cells. Although signaling pathways remain active throughout the cell cycle, their contribution to heterogeneous gene expression is restricted to G1. Surprisingly, we identify dramatic changes in the levels of global 5-hydroxymethylcytosine, an unanticipated source of epigenetic heterogeneity that is tightly linked to cell-cycle progression and the expression of developmental regulators. When we evaluated gene expression in differentiating cells, we found that cell-cycle regulation of developmental regulators was maintained during lineage specification. Cell-cycle regulation of developmentally regulated transcription factors is therefore an inherent feature of the mechanisms underpinning differentiation.
Highlights
•Embryonic stem cells are lineage primed in G1•Transcription of developmentally regulated genes is cell-cycle regulated•5hmC is cell-cycle regulated•Stem cells initiate differentiation from G1
Pluripotent stem cell heterogeneity has been attributed to stochastic variations in signaling pathways across the population. Using Fucci cell-cycle reporters, Dalton and colleagues show that stem cell “lineage priming” in G1 is associated with cell-cycle-dependent changes in the transcription of developmentally regulated genes. Moreover, these changes are paralleled by levels of the epigenetic mark 5-hydroxymethylcytosine. These findings identify the cell cycle as major source of heterogeneity in human pluripotent stem cells.
doi:10.1016/j.stemcr.2013.10.009
PMCID: PMC3871385  PMID: 24371808
24.  Upregulation of SOX9 in osteosarcoma and its association with tumor progression and patients’ prognosis 
Diagnostic Pathology  2013;8:183.
Objective
SOX9 plays an important role in bone formation and tumorigenesis. However, its involvement in osteosarcoma is still unclear. The aim of this study was to investigate the expression pattern and the clinical significance of SOX9 in human osteosarcoma.
Methods
SOX9 mRNA and protein expression levels were detected by RT-PCR and Western blot assays, respectively, using 30 pairs of osteosarcoma and noncancerous bone tissues. Then, immunohistochemistry was performed to analyze the association of SOX9 expression in 166 osteosarcoma tissues with clinicopathological factors or survival of patients.
Results
SOX9 expression at mRNA and protein levels were both significantly higher in osteosarcoma tissues than those in corresponding noncancerous bone tissues (both P < 0.001). Immunohistochemical staining indicated that SOX9 localized to the nucleus and high SOX9 expression was observed in 120 of 166 (72.3%) osteosarcoma specimens. In addition, high SOX9 expression was more frequently occurred in osteosarcoma tissues with advanced clinical stage (P = 0.02), positive distant metastasis (P = 0.008) and poor response to chemotherapy (P = 0.02). Osteosarcoma patients with high SOX9 expression had shorter overall survival and disease-free survival (both P < 0.001). Furthermore, the multivariate analysis confirmed that upregulation of SOX9 was an independent and significant prognostic factor to predict poor overall survival and disease-free survival (both P = 0.006).
Conclusions
Our data show for the first time that SOX9 is upregulated in aggressive osteosarcoma tissues indicating that SOX9 may participate in the osteosarcoma progression. More importantly, SOX9 status is a useful prognostic factor for predicting the prognosis of osteosarcoma, suggesting that SOX9 may contribute to the optimization of clinical treatments for osteosarcoma patients.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1318085636110837.
doi:10.1186/1746-1596-8-183
PMCID: PMC3829210  PMID: 24188461
Osteosarcoma; SOX9; Prognosis; Overall survival; Disease-free survival
25.  Association of Aggression and Non-Suicidal Self Injury: A School-Based Sample of Adolescents 
PLoS ONE  2013;8(10):e78149.
Purpose
Non-suicidal self-injury (NSSI) in adolescent has drawn increasing attention because it is associated with subsequent depression, drug abuse, anxiety disorders, and suicide. In the present study, we aimed to estimate the prevalence of non-suicidal self-injury (NSSI) in a school-based sample of Chinese adolescents and to explore the association between aggression and NSSI.
Methods
This study was part of a nationwide study on aggression among adolescents in urban areas of China. A sample of 2907 school students including 1436 boys and 1471 girls were randomly selected in Guangdong Province, with their age ranging from 10 to 18 years old. NSSI, aggression, emotional management and other factors were measured by self-administrated questionnaire. Multinomial logistic regression was used to estimate the association between aggression and NSSI, after adjustment for participants’ emotional management, and other potential confounding variables.
Results
The one year self-reported prevalence of NSSI was 33.6%. Of them, 21.7% engaged in ‘minor NSSI’, 11.9% in ‘moderate/severe NSSI’. 96.9% of self-injuries engaged in one to five different types of NSSI in the past year. Hostility, verbal and indirect aggression was significantly associated with self-reported NSSI after adjusting for other potential factors both in ‘minor NSSI’ and ‘moderate/severe NSSI’. Hostility, verbal and indirect aggression was significantly associated with greater risk of ‘minor NSSI’ and ‘moderate/severe NSSI’ in those who had poor emotional management ability.
Conclusion
These findings highlight a high prevalence of NSSI and indicate the importance of hostility, verbal and indirect aggression as potentially risk factor for NSSI among Chinese adolescents.
doi:10.1371/journal.pone.0078149
PMCID: PMC3813494  PMID: 24205132

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