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1.  Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer’s Disease 
PLoS ONE  2016;11(3):e0149945.
Sleep alleviates Alzheimer’s disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33–14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13–2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.
PMCID: PMC4777499  PMID: 26937653
2.  The Incidence Characteristics of Second Primary Malignancy after Diagnosis of Primary Colon and Rectal Cancer: A Population Based Study 
PLoS ONE  2015;10(11):e0143067.
With the expanding population of colorectal cancer (CRC) survivors in the United States, one concerning issue is the risk of developing second primary malignancies (SPMs) for these CRC survivors. The present study attempts to identify the incidence characteristics of SPMs after diagnosis of first primary colon cancer (CC) and rectal cancer (RC).
189,890 CC and 83,802 RC cases were identified from Surveillance, Epidemiology and End Results Program (SEER) database. We performed rate analysis on incidence trend of SPMs in both CC and RC. Expected incidence rates were stratified by age, race and stage, calendar year of first CRC diagnosis and latency period since first CRC diagnosis. The standardized incidence ratios (SIRs), measure for estimating risk of SPMs, were calculated for CC and RC respectively.
The trends of incidence of SPMs in both CC and RC were decreasing from 1992 to 2012. Both CC and RC survivors had higher risk of developing SPMs (SIRCC = 1.13; SIRRC = 1.05). For CC patients, the highest risks of SPM were cancers of small intestine (SIR = 4.03), colon (SIR = 1.87) and rectum (SIR = 1.80). For RC patients, the highest risks of SPMs were cancers of rectum (SIR = 2.88), small intestine (SIR = 2.16) and thyroid (SIR = 1.46). According to stratified analyses, we also identified incidence characteristics which were contributed to higher risk of developing SPMs, including the age between 20 and 40, American Indian/Alaska Native, localized stage, diagnosed at calendar year from 2002 to 2012 and the latency between 12 and 59 months.
Both CC and RC survivors remain at higher risk of developing SPMs. The identification of incidence characteristics of SPMs is extremely essential for continuous cancer surveillance among CRC survivors.
PMCID: PMC4646682  PMID: 26571301
3.  Enhanced Bioavailability and Anticancer Effect of Curcumin-Loaded Electrospun Nanofiber: In Vitro and In Vivo Study 
Nanofibers have attracted increasing attention in drug delivery and other biomedical applications due to their some special properties. The present study aims to prepare a fiber-based nanosolid dispersion system to enhance the bioavailability of curcumin (CUR). CUR-loaded polyvinyl pyrrolidone (CUR@PVP) nanofibers were successfully prepared via electrospinning. Scanning electron microscopy (SEM) was employed to observe the morphology of the nanofibers, and the SEM image showed that the drug-loaded nanofibers were smooth, and no CUR clusters were found on the surface of the nanofibers. The results of X-ray diffraction (XRD) demonstrated that the CUR was evenly distributed in the nanofibers in an amorphous state. Fourier transform infrared (FTIR) spectroscopy analysis indicated that intermolecular hydrogen bonding occurred between the CUR and the polymer matrix. In vitro dissolution profiles showed that CUR@PVP nanofiber could be quickly dissolved in phosphate-buffered saline (PBS) solution, while negligible dissolution was observed in pure CUR sample. Importantly, in vitro cell viability assays and in vivo animal tests revealed that the nanosolid dispersion system dramatically enhanced the bioavailability and showed effective anticancer effect of the CUR.
PMCID: PMC4646878  PMID: 26573930
Electrospinning; Curcumin; Bioavailability; Anticancer
4.  Changes in circulating lipids level over time after acquiring HCV infection: results from ERCHIVES 
BMC Infectious Diseases  2015;15:510.
Changes in lipid levels over time after acquiring HCV infection, and how they differ from HCV-uninfected persons are unknown.
We used ERCHIVES to identify those with a known HCV seroconversion window and persistently negative controls. We excluded subjects with HIV and hepatitis B and those who received lipid lowering agents. Total Cholesterol (TC), low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides (TG) and non-HDL cholesterol were retrieved at yearly intervals and plotted over time.
Among 1,270 HCV+ and 5,070 HCV- subjects, median age [IQR] was 47[37,53] for HCV+ and 52[47,57] for the HCV- group; 69 % were White and 91 % were males in each group. Mean BMI [SD] was 26.94[6.73] in the HCV+ and 28.15 [5.98] in the HCV- group (P < 0.001). Over a 10-year follow-up period among HCV+ persons, TC decreased by (mean (SD) mg/dL) 12.06(36.95), LDL by 9.22(31.44), TG by 13.58(87.01) and non-HDL-C by 12.55(35.14). Among HCV- persons, TC cholesterol decreased by 4.15(31.21), LDL by 4.16(26.51); TG by 4.42(82.34) and non-HDL-C by 5.78(30.17).
After HCV acquisition, TC, LDL, TG and non-HDL-C progressively decline over time independent of BMI and liver fibrosis. Consequences of lipid changes and the need and optimal timing of lipid lowering therapy in HCV+ persons require further study.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1268-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4642733  PMID: 26558512
HCV; Lipid; Cholesterol; LDL; ERCHIVES; Seroconversion
5.  Aspirin might reduce the incidence of pancreatic cancer: A meta-analysis of observational studies 
Scientific Reports  2015;5:15460.
Although there is evidence that non-steroidal anti-inflammatory drugs (NSAIDs) might be able to prevent pancreatic cancer, the findings from epidemiological studies have been inconsistent. In this paper, we conducted a meta-analysis of observational studies to examine this possibility. We searched PubMed and Embase for observational (cohort or case-control) studies examining the consumption of aspirin and other NSAIDs and the incidence of or mortality rates associated with pancreatic cancer. Twelve studies including approximately 258,000 participants in total were analysed. The administration of aspirin significantly reduced the incidence of pancreatic cancer (8 studies; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.62 to 0.96; I2 = 74.2%) but not the mortality associated with it (2 studies; OR = 0.94; 95% CI = 0.73 to 1.22). Specifically, frequent aspirin use was associated with reduced pancreatic cancer incidence (OR = 0.57; 95% CI = 0.39 to 0.83 for high frequency; OR = 0.57; 95% CI = 0.38 to 0.84 for medium frequency). The summary ORs regarding the incidence of pancreatic cancer and either non-aspirin NSAIDs use (OR = 1.08; 95% CI = 0.90 to 1.31) or overall NSAIDs use (OR = 0.97; 95% CI = 0.86 to 1.10) were not significant. In conclusion, aspirin use might reduce the incidence of pancreatic cancer; however, this finding should be interpreted with caution because of study heterogeneity.
PMCID: PMC4614261  PMID: 26486090
6.  Vicariance and Its Impact on the Molecular Ecology of a Chinese Ranid Frog Species-Complex (Odorrana schmackeri, Ranidae) 
PLoS ONE  2015;10(9):e0138757.
Paleogeological events and Pleistocene climatic fluctuations have had profound influences on the genetic patterns and phylogeographic structure of species in southern China. In this study, we investigated the population genetic structure and Phylogeography of the Odorrana schmackeri species complex, mountain stream-dwelling odorous frogs, endemic to southern China. We obtained mitochondrial sequences (1,151bp) of the complete ND2 gene and two flanking tRNAs of 511 individuals from 25 sites for phylogeographic analyses. Phylogenetic reconstruction revealed seven divergent evolutionary lineages, with mean pairwise (K2P) sequence distances from 7.8% to 21.1%, except for a closer ND2 distance (3.4%). The complex geological history of southern China drove matrilineal divergence in the O. schmackeri species complex into highly structured geographical units. The first divergence between lineage A+B and other lineages (C-G) had likely been influenced by the uplift of coastal mountains of Southeast China during the Mio-Pliocene period. The subsequent divergences between the lineages C-G may have followed the formation of the Three Gorges and the intensification of the East Asian summer monsoon during the late Pliocene and early Pleistocene. Demographic analyses indicated that major lineages A and C have been experienced recent population expansion (c. 0.045–0.245 Ma) from multiple refugia prior to the Last Glacial Maximum (LGM). Molecular analysis suggest that these seven lineages may represent seven different species, three described species and four cryptic species and should at least be separated into seven management units corresponding to these seven geographic lineages for conservation.
PMCID: PMC4578928  PMID: 26394403
7.  Analysis of high risk factors and characteristics of coronary artery in premenopausal women with coronary artery disease 
Objective: The aim of this study was to explore the high risk factors and coronary lesion features in premenopausal women with coronary artery disease (CAD) and provide guideline for diagnosis and therapy. Methods: 114 premenopausal women and 134 postmenopausal women were conducted coronary angiography in our hospital from September, 2012 to September, 2014. According to the results of coronary angiography, premenopausal and postmenopausal women with coronary artery disease were divided into two groups respectively, including 48 premenopausal women with CAD group, 66 premenopausal women with normal coronary artery group, 76 postmenopausal women with CAD group and 58 postmenopausal women with normal coronary artery group. Clinical characteristics and coronary lesion features were analyzed. Results: Incidence rates of hypertension disease and diabetes were higher in premenopausal women with CAD group than control group. Most of premenopausal women suffered from single vessel lesion and the length of impaired vessel was less than 20 mm, meanwhile, postmenopausal women easily confronted from double vessels or mutivessle lesion and the length of impaired vessel was more than 20 mm. Left anterior descending coronary artery lesion was common for premenopausal women. Conclusion: Hypertension disease and diabetes were the main high risk factors for premenopausal women and high triglyceride was the optimal predictable factor, furthermore, single vessel lesion and short artery lesion were common in premenopausal women, which often happened in the anterior descending coronary artery.
PMCID: PMC4659063  PMID: 26629175
CAD; premenopause; coronary angiography; coronary artery feature; risk factor
8.  Antitumor Activity of Doxorubicin-Loaded Carbon Nanotubes Incorporated Poly(Lactic-Co-Glycolic Acid) Electrospun Composite Nanofibers 
The drug-loaded composite electrospun nanofiber has attracted more attention in biomedical field, especially in cancer therapy. In this study, a composite nanofiber was fabricated by electrospinning for cancer treatment. Firstly, the carbon nanotubes (CNTs) were selected as carriers to load the anticancer drug—doxorubicin (DOX) hydrochloride. Secondly, the DOX-loaded CNTs (DOX@CNTs) were incorporated into the poly(lactic-co-glycolic acid) (PLGA) nanofibers via electrospinning. Finally, a new drug-loaded nanofibrous scaffold (PLGA/DOX@CNTs) was formed. The properties of the prepared composite nanofibrous mats were characterized by various techniques. The release profiles of the different DOX-loaded nanofibers were measured, and the in vitro antitumor efficacy against HeLa cells was also evaluated. The results showed that DOX-loaded CNTs can be readily incorporated into the nanofibers with relatively uniform distribution within the nanofibers. More importantly, the drug from the composite nanofibers can be released in a sustained and prolonged manner, and thereby, a significant antitumor efficacy in vitro is obtained. Thus, the prepared composite nanofibrous mats are a promising alternative for cancer treatment.
PMCID: PMC4549354  PMID: 26306537
Electrospun nanofiber; Poly(lactic-co-glycolic acid); Carbon nanotubes; Drug release; Antitumor efficacy
9.  A Novel Bio-carrier Fabricated Using 3D Printing Technique for Wastewater Treatment 
Scientific Reports  2015;5:12400.
The structure of bio-carriers is one of the key operational characteristics of a biofilm reactor. The goal of this study is to develop a series of novel fullerene-type bio-carriers using the three-dimensional printing (3DP) technique. 3DP can fabricate bio-carriers with more specialized structures compared with traditional fabrication processes. In this research, three types of fullerene-type bio-carriers were fabricated using the 3DP technique and then compared with bio-carrier K3 (from AnoxKaldnes) in the areas of physicochemical properties and biofilm growth. Images acquired by 3D profiling and SEM indicated that the surface roughness of the 3DP bio-carrier was greater than that of K3. Furthermore, contact angle data indicated that the 3DP bio-carriers were more hydrophilic than K3. The biofilm on the 3DP bio-carriers exhibited higher microbial activity and stronger adhesion ability. These findings were attributed to excellent mass transfer of the substrate (and oxygen) between the vapour-liquid-solid tri-phase system and to the surface characteristics. It is concluded that the novel 3DP fullerene-type bio-carriers are ideal carriers for biofilm adherence and growth.
PMCID: PMC4648452  PMID: 26202477
10.  Extracellular protein analysis of activated sludge and their functions in wastewater treatment plant by shotgun proteomics 
Scientific Reports  2015;5:12041.
In this work, proteins in extracellular polymeric substances extracted from anaerobic, anoxic and aerobic sludges of wastewater treatment plant (WWTP) were analyzed to probe their origins and functions. Extracellular proteins in WWTP sludges were identified using shotgun proteomics, and 130, 108 and 114 proteins in anaerobic, anoxic and aerobic samples were classified, respectively. Most proteins originated from cell and cell part, and their most major molecular functions were catalytic activity and binding activity. The results exhibited that the main roles of extracellular proteins in activated sludges were multivalence cations and organic molecules binding, as well as in catalysis and degradation. The catalytic activity proteins were more widespread in anaerobic sludge compared with those in anoxic and aerobic sludges. The structure difference between anaerobic and aerobic sludges could be associated with their catalytic activities proteins. The results also put forward a relation between the macro characteristics of activated sludges and micro functions of extracellular proteins in biological wastewater treatment process.
PMCID: PMC4498230  PMID: 26160685
11.  Characterization of SMAD3 Gene Variants for Possible Roles in Ventricular Septal Defects and Other Congenital Heart Diseases 
PLoS ONE  2015;10(6):e0131542.
Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD).
We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5’UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.
Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5’UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05).
The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations.
PMCID: PMC4482402  PMID: 26110764
12.  MicroRNA-26b inhibits cell proliferation and cytokine secretion in human RASF cells via the Wnt/GSK-3β/β-catenin pathway 
Diagnostic Pathology  2015;10:72.
Rheumatoid arthritis (RA) is a chronic systemic auto- immune disease characterized by joint synovitis. Recent evidence suggests that rheumatoid arthritis synovial fibroblasts (RASFs) promote joint destruction. In this study, we investigated the role of microRNA-26b (miR-26b) in cell proliferation and inflammatory cytokine secretion using patient-derived Rheumatoid arthritis fibroblast-like synoviocyte (RAFLS) to understand pathways influencing rheumatoid arthritis.
RAFLS were cultured in vitro and transfected with miR-26b mimics (experimental group) and negative sequence (control group). The protein levels of Wnt4, Wnt5ɑ, GSK-3β, CyclinD1, Ser9-GSK-3β and β-catenin were detected by western blot analysis. Tumor Necrosis Factor-ɑ (TNF-ɑ), IL- 1β, and IL-6 levels were quantified by Enzyme-linked Immunosorbent Assay (ELISA). RAFLS proliferation and apoptosis were measured by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry, respectively.
GSK-3β and CyclinD1 expression levels were lower in miR-26b mimic group compared to Mock group and negative control (NC) group. Conversely, GSK-3β and CyclinD1 expression levels were markedly higher in the miR-26b inhibitor group compared to Mock and NC group (P < 0.05). Transfection of miR-26b mimics significantly increased the, levels of Ser9-GSK-3β and β-catenin in comparison to Mock and NC groups, while transfection of miR-26b inhibitors showed the opposite effect. In miR-26b mimic group, TNF-α, IL- 1β and IL-6 levels were lower than the Mock and NC groups, while in miR-26b inhibitor group, these cytokine levels were higher than the Mock and NC groups (P < 0.05). Transfection of miR-26b mimics significantly reduced the cell proliferation of RAFLS, compared to the Mock and NC groups, and miR-26b inhibitors increased the proliferative capacity of RAFLS compared to Mock and NC groups (P < 0.05). The miR-26b mimic group exhibited higher RAFLS apoptosis rate compared to Mock and NC group and miR-26b inhibitor group showed significantly lower RAFLS apoptosis rate compared to Mock and NC groups (P < 0.05).
MiR-26b regulates β-catenin and CyclinD1 levels by inhibiting GSK-3β expression, which in-turn alters the Wnt/GSK-3β/β-catenin pathway to lower RAFLS proliferation and elevate cell apoptosis and the secretion of TNF-α,IL-1β and IL-6 cytokines. Therefore, our results show that miR-26B plays a central role in inhibiting the inflammation associated with rheumatoid arthritis.
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PMCID: PMC4472173  PMID: 26088648
MicroRNA-26b; Rheumatoid arthritis; Wnt/GSK-3β/β-catenin pathway; CyclinD1; Cytokine
13.  Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0129450.
Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05–3.30) using a random-effects model (I2 = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73–0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67–0.82) and 0.64 (95% CI, 0.52–0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35–3.95) using a fixed-effects model (I2 = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75–0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58–0.82) and 0.77 (95% CI, 0.55–0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.
PMCID: PMC4468164  PMID: 26076027
14.  Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload 
Neural Regeneration Research  2015;10(5):778-785.
Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer’s disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer’s disease patients. An APPswe/PS1ΔE9 double transgenic mouse model of Alzheimer’s disease was used. The intragastric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer’s disease. These compounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer’s disease.
PMCID: PMC4468770  PMID: 26109953
nerve regeneration; neurodegenerative diseases; Alzheimer's disease; transgenic animal models; mice; epimedium herb; milkvetch root; kudzuvine root; divalent metal transporter 1; ferroportin 1; neural regeneration
15.  Single Chain Variable Fragment Against Aβ Expressed in Baculovirus Inhibits Abeta Fibril Elongation and Promotes its Disaggregation 
PLoS ONE  2015;10(4):e0124736.
Alzheimer’s disease (AD) is the most common form of age-related dementia, and the most urgent problem is that it is currently incurable. Amyloid-β (Aβ) peptide is believed to play a major role in the pathogenesis of AD. We previously reported that an Aβ N-terminal amino acid targeting monoclonal antibody (MAb), A8, inhibits Aβ fibril formation and has potential as an immunotherapy for AD based on a mouse model. To further study the underlying mechanisms, we tested our hypothesis that the single chain fragment variable (scFv) without the Fc fragment is capable of regulating either Aβ aggregation or disaggregation in vitro. Here, a model of cell-free Aβ “on-pathway” aggregation was established and identified using PCR, Western blot, ELISA, transmission electron microscopy (TEM) and thioflavin T (ThT) binding analyses. His-tagged A8 scFvs was cloned and solubly expressed in baculovirus. Our data demonstrated that the Ni-NTA agarose affinity-purified A8 scFv inhibited the forward reaction of “on-pathway” aggregation and Aβ fibril maturation. The effect of A8 scFv on Aβ fibrillogenesis was markedly more significant when administered at the start of the Aβ folding reaction. Furthermore, the results also showed that pre-formed Aβ fibrils could be disaggregated via incubation with purified A8 scFv, which suggested that A8 scFv is involved in the reverse reaction of Aβ aggregation. Therefore, A8 scFv was capable of both inhibiting fibrillogenesis and disaggregating matured fibrils. Our present study provides valuable insight into the regulators of ultrastructural dynamics of cell-free “on-pathway” Aβ aggregation and will assist in the development of therapeutic strategies for AD.
PMCID: PMC4412524  PMID: 25919299
16.  Dynamic Changes in Amino Acid Concentration Profiles in Patients with Sepsis 
PLoS ONE  2015;10(4):e0121933.
The goal of this work was to explore the dynamic concentration profiles of 42 amino acids and the significance of these profiles in relation to sepsis, with the aim of providing guidance for clinical therapies.
Thirty-five critically ill patients with sepsis were included. These patients were further divided into sepsis (12 cases) and severe sepsis (23 cases) groups or survivor (20 cases) and non-survivor (15 cases) groups. Serum samples from the patients were collected on days 1, 3, 5, 7, 10, and 14 following intensive care unit (ICU) admission, and the serum concentrations of 42 amino acids were measured.
The metabolic spectrum of the amino acids changed dramatically in patients with sepsis. As the disease progressed further or with poor prognosis, the levels of the different amino acids gradually increased, decreased, or fluctuated over time. The concentrations of sulfur-containing amino acids (SAAs), especially taurine, decreased significantly as the severity of sepsis worsened or with poor prognosis of the patient. The serum concentrations of SAAs, especially taurine, exhibited weak negative correlations with the Sequential Organ Failure Assessment (SOFA) (r=-0.319) and Acute Physiology and Chronic Health Evaluation (APACHE) II (r=-0.325) scores. The areas under the receiver operating characteristic curves of cystine, taurine, and SAA levels and the SOFA and APACHE II scores, which denoted disease prognosis, were 0.623, 0.674, 0.678, 0.86, and 0.857, respectively.
Critically ill patients with disorders of amino acid metabolism, especially of SAAs such as cystine and taurine, may provide an indicator of the need for the nutritional support of sepsis in the clinic.
Trial Registration identifier NCT01818830.
PMCID: PMC4388841  PMID: 25849571
17.  Prognostic value of different scoring models in patients with multiple organ dysfunction syndrome associated with acute COPD exacerbation 
Journal of Thoracic Disease  2015;7(3):329-336.
Background and objective
Chronic obstructive pulmonary disease (COPD) represents an increasing healthcare concern as a leading cause of morbidity and mortality worldwide. Our objective was to predict the outcome of COPD patients associated with multiple organ dysfunction syndrome (MODS) by scoring models.
A retrospective study was performed on severe COPD patients within 24 hours of the onset of MODS. The Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, Multiple Organ Dysfunction Score (MODS), Simplified Acute Physiology Score II (SAPS II), and Sepsis-related Organ Failure Assessment (SOFA) scores were calculated for patients.
A total of 153 elderly patients were recruited. Compared to 30-day survivors, the number of failing organs and all of the scoring models were significantly higher in 30-day non-survivors. The SOFA showed the highest sensitivity and area under the curve (AUC) for predicting the prognosis of patients with MODS induced by acute exacerbation of COPD. The results of logistic regression indicated that factors that were correlated with the prognosis of COPD included the exacerbation history, SOFA score, number of failing organs, and duration of ICU stay. The value of exacerbation frequency for predicting the outcome of COPD was excellent (AUC: 0.892), with a sensitivity of 0.851 and a specificity of 0.797.
The SOFA score, determined at the onset of MODS in elderly patients with COPD, was a reliable predictor of the prognosis. The exacerbation frequency, number of failing organs, and the SOFA score were risk factors of a poor prognosis, and the exacerbation frequency could also effectively predict the outcome of COPD.
PMCID: PMC4387415  PMID: 25922710
Acute exacerbation (AE); chronic obstructive pulmonary disease (COPD); multiple organ dysfunction syndrome (MODS); prognosis
18.  Crystal structure of human Fanconi-associated nuclease 1 
Protein & Cell  2014;6(3):225-228.
PMCID: PMC4348246  PMID: 25547363
19.  Crystal structure of human Fanconi-associated nuclease 1 
Protein & Cell  2014;6(3):225-228.
PMCID: PMC4348246  PMID: 25547363
20.  Statin Therapy Decreased the Recurrence Frequency of Atrial Fibrillation after Electrical Cardioversion: A Meta-Analysis 
It is unclear whether statin agents provide clinical benefit in preventing the relapse of atrial fibrillation (AF) after electrical cardioversion (EC). The purpose of this study was to assess the effect of statin agents on the recurrence of AF after EC by conducting a meta-analysis of randomized controlled trials (RCTs).
We conducted a systematic literature search of Medline, EMBASE, ISI Web of Science, and Cochrane databases. RCTs comparing clinical endpoint of the recurrence of AF associated with statin administration vs. no statin treatment (placebo or conventional medical therapy) in patients with AF after EC were eligible. Combined results are presented as risk ratios (RRs) with 95% confidence intervals (CIs).
A total of 5 trials with 524 patients were available for analysis. The pooling analysis showed that statin agents significantly reduced the recurrence of AF after EC compared with no statin treatment (RR=0.76, 95% CI 0.63–0.92; p=0.004; I2=44%). The beneficial effect was shown both in AF subjects receiving atorvastatin or rosuvastatin treatment (atorvastatin 80 mg: RR=0.82, p=0.05; atorvastatin 10 mg: RR=0.27, p=0.03; rosuvastatin: RR=0.38, p=0.04) and in younger patients (<65 years; RR=0.58, p=0.0005). Furthermore, the benefit of statin agents on preventing AF recurrence after EC was demonstrated within 3-month follow-up (p=0.03), and the clinical benefit seemed likely to remain until no less than 12 months after EC (p=0.05).
Based on the currently available data, administration of statin agents, especially atorvastatin or rosuvastatin, is beneficial in lowering the frequency of AF recurrence after EC.
PMCID: PMC4280056  PMID: 25529758
Atrial Fibrillation; Electric Countershock; Hydroxymethylglutaryl-CoA Reductase Inhibitors
21.  Association between vitamin D deficiency and mortality in critically ill adult patients: a meta-analysis of cohort studies 
Critical Care  2014;18(6):684.
Vitamin D deficiency is common in critically ill patients, and was reported to be associated with adverse outcomes. However, the effect of vitamin D deficiency on mortality in critically ill patients remains unclear.
We searched PubMed and EMBASE from the inception to July 2014 for cohort studies to assess the effect of vitamin D deficiency on the incidence of mortality in critically ill patients. Mortality-specific odds ratio (OR) with 95% confidence interval (CI) were pooled with a random- or fixed-effect models when appropriate.
Seven cohort studies with a total of 4,204 participants including 1,679 cases of vitamin D deficiency were included in this meta-analysis. Vitamin D deficiency was significantly associated with an increased hospital mortality (OR 1.76; 95% CI, 1.38 to 2.24; P <0.001), with very low heterogeneity (I2 = 2.3%; P = 0.402). The finding of increased hospital mortality in critically ill adult patients was consistently found in every stratum of our subgroup analyses.
This meta-analysis suggests that vitamin D deficiency is associated with increased incidence of hospital mortality in critically ill adult patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0684-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4274763  PMID: 25498305
22.  Discrimination of sepsis stage metabolic profiles with an LC/MS-MS-based metabolomics approach 
BMJ Open Respiratory Research  2014;1(1):e000056.
To identify metabolic biomarkers that can be used to differentiate sepsis from systemic inflammatory response syndrome (SIRS), assess severity and predict outcomes.
65 patients were involved in this study, including 35 patients with sepsis, 15 patients with SIRS and 15 normal patients. Small metabolites that were present in patient serum samples were measured by liquid chromatography mass spectrometry techniques and analysed using multivariate statistical methods.
The metabolic profiling of normal patients and patients with SIRS or sepsis was markedly different. A significant decrease in the levels of lactitol dehydrate and S-phenyl-d-cysteine and an increase in the levels of S-(3-methylbutanoyl)-dihydrolipoamide-E and N-nonanoyl glycine were observed in patients with sepsis in comparison to patients with SIRS (p<0.05). Patients with severe sepsis and septic shock displayed lower levels of glyceryl-phosphoryl-ethanolamine, Ne, Ne dimethyllysine, phenylacetamide and d-cysteine (p<0.05) in their sera. The profiles of patients with sepsis 48 h before death illustrated an obvious state of metabolic disorder, such that S-(3-methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z, 16Z)/0:0), glycerophosphocholine and S-succinyl glutathione were significantly decreased (p<0.05). The receiver operating characteristic curve of the differential expression of these metabolites was also performed.
The body produces significant evidence of metabolic disorder during SIRS or sepsis. Seven metabolites may potentially be used to diagnose sepsis.
Trial registration number identifier NCT01649440.
PMCID: PMC4265126  PMID: 25553245
Respiratory Infection
23.  Advantages of CyberKnife for inoperable stage I peripheral non-small-cell lung cancer compared to three-dimensional conformal radiotherapy 
Molecular and Clinical Oncology  2014;3(2):442-448.
This study was conducted to compare the clinical curative effect and acute radiation lung reactions between CyberKnife (CK) and three-dimensional conformal radiotherapy (3DCRT) treatment for inoperable stage I peripheral non-small-cell lung cancer (NSCLC). We retrospectively analyzed 68 patients with inoperable stage I peripheral NSCLC between 2012 and 2013 in our institution. The CK patients were treated with 42–60 Gy in three fractions, while the 3DCRT patients were treated with a total of 60 Gy, at 2 Gy per fraction. The patients were followed up and the clinical outcome was evaluated according to the Response Evaluation Criteria in Solid Tumours. We assessed the presence of acute radiation pneumonitis and pulmonary function status by thoracic scan and pulmonary function tests following CK and 3DCRT treatment. The binary univariate logistic regression analysis demonstrated that treatment method and forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) prior to treatment (pre-FEV1/FVC) were the main factors affecting the risk of radiation pneumonitis. The analysis of these factors through multivariate logistic regression method demonstrated that treatment method for grade 1 and 2 [odds ratio (OR)= 7.866 and 11.334, respectively) and pre-FEV1/FVC for grade 1, 2 and 3 (OR = 5.062, 11.498 and 15.042, respectively) were significant factors affecting the risk of radiation pneumonitis (P<0.05). The 68 patients were divided into two subgroups using the threshold of pre-FEV1/FVC selected by the receiver operating characteristic curve. There were significant differences between the 3DCRT and CK treatment in both the pre-FEV1/FVC <68% and ≥68% subgroups for radiation pneumonitis (P=0.023 and 0.002, respectively). There was no statistically significant change in FVC, FEV1 and carbon monoxide diffusion capacity (DCLO) in the CK group, whereas there was a decrease in DCLO in the 3DCRT group. The complete remission rate was 40 vs. 34.2% at 1 year in the CK and 3DCRT groups, respectively. In conclusion, in this cohort of patients with inoperable stage I peripheral NSCLC, CK appears to be a safe and superior alternative to conventionally fractionated radiotherapy.
PMCID: PMC4360859  PMID: 25798283
CyberKnife; three-dimensional conformal radiotherapy; non-small-cell lung cancer; radiation pneumonitis
24.  High expression of microRNA-130b correlates with poor prognosis of patients with hepatocellular carcinoma 
Diagnostic Pathology  2014;9:160.
Whether microRNA-130b(miR-130b) can serve as a prognostic biomarker of hepatocellular carcinoma (HCC) has not been investigated. In the present study, we investigated the feasibility of miR-130b as a novel prognostic biomarker for HCC.
We retrospectively investigated 97 patients diagnosed with HCC who underwent routine curative surgery between May 2007 and July 2012. miR-130b expression in HCC tissues and paired normal adjacent liver tissues was measured by reverse transcription and real-time PCR (RT-PCR). Survival curves were plotted using the Kaplan-Meier method and differences in survival rates were analyzed using the log-rank test.
miR-130b expression level was significantly higher in HCC tissues compared with normal adjacent liver tissues (P < 0.0001). The 5-year overall survival (OS) of high miR-130b expression group was significantly shorter than that of low miR-130b expression group (43.6% vs. 71.5%; P = 0.022). Moreover, the 5-year disease-free survival (DFS) of high miR-130b expression group was also significantly shorter than that of low miR-130b expression group (25.9% vs. 63.9%; P = 0.012). In a multivariate Cox model, we found that miR-130b expression was an independent prognostic factor for both 5-year OS (hazards ratio [HR] = 2.523, 95% confidence interval [CI] = 1.024-7.901, P = 0.011) and 5-year DFS (HR = 4.003, CI = 1.578-7.899, P = 0.005) in HCC.
The results indicated that high expression of microRNA-130b was correlated with significant characteristics of patients with HCC, and it might be useful as a novel prognostic biomarker for HCC.
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PMCID: PMC4141946  PMID: 25123453
25.  Characterization of Nodal/TGF-Lefty Signaling Pathway Gene Variants for Possible Roles in Congenital Heart Diseases 
PLoS ONE  2014;9(8):e104535.
Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD).
We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software.
Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A) variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.016<0.05). The genotype frequency of rs360057 (g.A1035C) variant in Lefty1 gene was associated with the risk of CHD (P value = 0.007<0.05), but the allele frequency was not (P value = 0.317>0.05).
The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.
PMCID: PMC4128709  PMID: 25111179

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