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2.  Identification and Susceptibility of Aspergillus Section Nigri in China: Prevalence of Species and Paradoxical Growth in Response to Echinocandins 
Journal of Clinical Microbiology  2014;53(2):702-705.
Molecular identification and in vitro antifungal susceptibility tests of 43 Aspergillus section Nigri isolates from China were performed. Aspergillus niger and Aspergillus tubingensis were present in almost equal numbers. All of the isolates had low MIC/MECs (minimum effective concentrations) for the 7 common antifungals, and a paradoxical effect was observed for the first time in response to caspofungin and micafungin.
doi:10.1128/JCM.03233-14
PMCID: PMC4298494  PMID: 25502526
3.  Human Adenovirus Type 7 Infection Associated with Severe and Fatal Acute Lower Respiratory Illness and Nosocomial Transmission 
Journal of Clinical Microbiology  2014;53(2):746-749.
A 23-year-old male died of severe pneumonia and respiratory failure in a tertiary hospital in Beijing, and 4 out of 55 close contacts developed fever. Molecular analysis confirmed human adenovirus type 7 (HAdV7) as the causative agent. We highlight the importance of early diagnosis and treatment and proper transmission control of HAdV7.
doi:10.1128/JCM.02517-14
PMCID: PMC4298532  PMID: 25520444
4.  Synergistic Activity of Chloroquine with Fluconazole against Fluconazole-Resistant Isolates of Candida Species 
The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.
doi:10.1128/AAC.04417-14
PMCID: PMC4335839  PMID: 25512426
5.  Superior efficacy of rituximab-based chemoimmunotherapy as an initial therapy in newly diagnosed patients with B cell indolent lymphomas: long-term results from a single center in China 
BMC Cancer  2015;15:555.
Background
Rituximab has been confirmed to improve the survival of patients with B cell indolent non-Hodgkin lymphomas (B-iNHLs) in Western world as previously reported, however, it is rarely reported in Chinese cohort. This study is to investigate the efficacy and safety of rituximab-based chemoimmunotherapy and select subpopulations most sensitive to the regimen in Chinese B-iNHL patients.
Methods
334 B-iNHL patients from our center were retrospectively assessed.
Results
Patients received R-based chemoimmunotherapy showed significantly higher rates of overall response (OR) (93.0 % vs. 53.4 %, P < 0.001) and complete response (CR) (63.3 % vs. 16.0 %, P < 0.001) compared with the patients received other therapies. Survival analysis showed that rituximab-based chemoimmunotherapy could obviously improve the progression-free survival (PFS) (110 vs. 49 months, P = 0.001) and overall survival (OS) (120 vs. 72 months, P < 0.001) in patients with B-iNHLs. Interestingly, in chronic lymphocytic leukemia (CLL) patients, we found that the patients with β2-microglobulin (β2-MG) < 3.5 mg/L, lactate dehydrogenase (LDH) < 220 U/L, zeta-chain-associated protein kinase 70 (ZAP-70) negative, and non high-risk genetic abnormality could achieve more benefits from R-based regimens with higher CR rate (P = 0.003, 0.029, 0.013 and 0.038, respectively). Meanwhile, more CLL patients achieved minimal residual disease (MRD) negative after rituximab-based treatment (46.5 % vs. 10.3 %, P < 0.001). Moreover, CLL patients with MRD < 1 %, LDH < 220 U/L, complete remission (CR) or partial remission (PR), β2-MG < 3.5 mg/L and non high-risk cytogenetic abnormality showed superior outcome compared to the controls (P = 0.001, 0.000, 0.000, 0.001 and 0.013, respectively). No other side-effects increased in chemoimmunotherapy group except the elevation of grade 3–4 neutropenia.
Conclusions
Our results demonstrate the superior efficacy of rituximab–based chemoimmunotherapy as an initial therapy in Chinese cohort with newly diagnosed B-iNHLs and further identify subpopulations that are more sensitive to R-based chemoimmunotherapy in CLL group.
doi:10.1186/s12885-015-1534-0
PMCID: PMC4517647  PMID: 26219471
B cell indolent lymphoma; Chronic lymphocytic leukemia; Rituximab; Chemoimmunotherapy; Prognosis
6.  Pulmonary Function and Clinical Manifestations of Patients Infected with Mild Influenza A Virus Subtype H1N1: A One-Year Follow-Up 
PLoS ONE  2015;10(7):e0133698.
Objective
To investigate the long-term effects of mild H1N1 influenza infection on the pulmonary function of a cohort of patients.
Methods
Forty-eight patients, all diagnosed with influenza A virus subtype H1N1 in 2009, were retrospectively included in this study. Each patient in the study was monitored for 11-13 months by standard pulmonary function examination. The examination included monitoring respiratory tract infection symptoms (cough, expectoration or gasping) and vital signs. Long-term changes in symptoms and changes in vital signs were correlated back to and compared with the severity of the initial H1N1 influenza infection.
Results
One year post discharge, mild to moderate pulmonary dysfunction was observed in the majority of patients. Further, 54.2% of patients had signs of severe abnormal pulmonary function, including diffusion disorder (33.3%) and small airway dysfunction (33.3%). Fourteen patients presented with respiratory tract infection symptoms; 12 with abnormal pulmonary function and two with normal pulmonary function. Our results indicated that the change in pulmonary function at one year post discharge was not significantly correlated with the severity of H1N1 influenza.
Conclusion
Signs and symptoms of abnormal pulmonary function accompanied by respiratory tract infection symptoms remain for some patients after one year following discharge from the hospital for mild influenza A virus subtype H1N1 infection. These patients should continue to be monitored for any changes in condition and symptoms and rehabilitation treatment should be provided when necessary.
doi:10.1371/journal.pone.0133698
PMCID: PMC4517883  PMID: 26218647
7.  Microbiota of Healthy Corals Are Active against Fungi in a Light-Dependent Manner 
ACS Chemical Biology  2014;9(10):2300-2308.
Coral reefs are intricate ecosystems that harbor diverse organisms, including 25% of all marine fish. Healthy corals exhibit a complex symbiosis between coral polyps, endosymbiotic alga, and an array of microorganisms, called the coral holobiont. Secretion of specialized metabolites by coral microbiota is thought to contribute to the defense of this sessile organism against harmful biotic and abiotic factors. While few causative agents of coral diseases have been unequivocally identified, fungi have been implicated in the massive destruction of some soft corals worldwide. Because corals are nocturnal feeders, they may be more vulnerable to fungal infection at night, and we hypothesized that the coral microbiota would have the capability to enhance their defenses against fungi in the dark. A Pseudoalteromonas sp. isolated from a healthy octocoral displayed light-dependent antifungal properties when grown adjacent to Penicilliumcitrinum (P. citrinum) isolated from a diseased Gorgonian octocoral. Microbial MALDI-imaging mass spectrometry (IMS) coupled with molecular network analyses revealed that Pseudoalteromonas produced higher levels of antifungal polyketide alteramides in the dark than in the light. The alteramides were inactivated by light through a photoinduced intramolecular cyclization. Further NMR studies led to a revision of the stereochemical structure of the alteramides. Alteramide A exhibited antifungal properties and elicited changes in fungal metabolite distributions of mycotoxin citrinin and citrinadins. These data support the hypothesis that coral microbiota use abiotic factors such as light to regulate the production of metabolites with specialized functions to combat opportunistic pathogens at night.
doi:10.1021/cb500432j
PMCID: PMC4201335  PMID: 25058318
8.  Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent 
The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase–ligand interaction space in the PDB.
doi:10.2147/DDDT.S85357
PMCID: PMC4517520
EGFR; kinase; inhibitor; protein crystal complex; FBDD; erlotinib
9.  Tissue microRNA-126 expression level predicts outcome in human osteosarcoma 
Diagnostic Pathology  2015;10:116.
Background
MicroRNA-126 has been found to be consistently under-expressed in osteosarcoma tissues and cell lines compared with normal bone tissues and normal osteoblast cells, respectively. The purpose of the present study was to detect the expression levels of miR-126 in osteosarcoma patients and to further investigate the clinicopathological, and prognostic value of miR-126.
Methods
We recruited 122 patients with osteosarcomas from the Department of Orthopedic Surgery, Yantaishan Hospital between May 2008 and April 2013. The expression level of miR-126 was determined by qRT-PCR. Associations between miR-126 expression and various clinicopathological characteristics were analyzed using the χ2 test. Survival rate was determined with Kaplan-Meier and statistically analyzed with the log-rank method between groups. Survival data were evaluated through multivariate Cox regression analysis.
Results
miR-126 expression was significantly decreased in osteosarcoma tissues compared to adjacent normal bone tissues (2.421 ± 1.250 vs. 6.212 ± 1.843, P = 0.001). We found that low miR-126 expression had significant association with advanced TNM stage (P <0.001), distant metastasis (P <0.001), and higher tumor grade (P = 0.001). Kaplan-Meier survival analysis showed that the miR-126 low-expression group had significantly shorter overall survival time than those with high-expression (log-rank test, P = 0.008). Furthermore, multivariate Cox proportional hazards model analysis showed that miR-126 expression was independently associated with overall survival of patients with osteosarcoma (HR = 3.102, 95 % CI: 1.113–9.023, P = 0.018).
Conclusions
This is the first study revealing that miR-126 down-expression may be related to the prediction of poor prognosis for osteosarcoma patients, suggesting that miR-126 may serve as a prognostic marker for the optimization of clinical treatments.
doi:10.1186/s13000-015-0329-6
PMCID: PMC4509614  PMID: 26194657
Osteosarcoma; microRNA; miR-126; Prognosis
10.  Femtosecond crystallography of membrane proteins in the lipidic cubic phase 
Despite recent technological advances in heterologous expression, stabilization and crystallization of membrane proteins (MPs), their structural studies remain difficult and require new transformative approaches. During the past two years, crystallization in lipidic cubic phase (LCP) has started gaining a widespread acceptance, owing to the spectacular success in high-resolution structure determination of G protein-coupled receptors (GPCRs) and to the introduction of commercial instrumentation, tools and protocols. The recent appearance of X-ray free-electron lasers (XFELs) has enabled structure determination from substantially smaller crystals than previously possible with minimal effects of radiation damage, offering new exciting opportunities in structural biology. The unique properties of LCP material have been exploited to develop special protocols and devices that have established a new method of serial femtosecond crystallography of MPs in LCP (LCP-SFX). In this method, microcrystals are generated in LCP and streamed continuously inside the same media across the intersection with a pulsed XFEL beam at a flow rate that can be adjusted to minimize sample consumption. Pioneering studies that yielded the first room temperature GPCR structures, using a few hundred micrograms of purified protein, validate the LCP-SFX approach and make it attractive for structure determination of difficult-to-crystallize MPs and their complexes with interacting partners. Together with the potential of femtosecond data acquisition to interrogate unstable intermediate functional states of MPs, LCP-SFX holds promise to advance our understanding of this biomedically important class of proteins.
doi:10.1098/rstb.2013.0314
PMCID: PMC4052856  PMID: 24914147
lipidic cubic phase; X-ray free-electron laser; G protein-coupled receptor; membrane proteins; serial femtosecond crystallography
11.  Multi-field Optimization Intensity-Modulated Proton Therapy for Head and Neck Tumors – A Translation to Practice 
Summary
The first fifteen consecutive patients treated with multi-field optimization intensity modulated proton therapy (MFO-IMPT) were able to complete treatment with no need for treatment breaks and no hospitalizations. Ten patients presented with SCC and 5 with ACC. There were no treatment-related deaths and with a median follow-up of 28 months, the overall clinical complete response rate was 93.3%. Early clinical outcomes warrant further investigation of proton therapy in the management of head and neck malignancies.
Background
We report the first clinical experience and toxicity of multi-field optimization (MFO) intensity-modulated proton therapy (IMPT) for patients with head and neck tumors.
Methods
Fifteen consecutive patients with head and neck cancer underwent MFO-IMPT with active scanning beam proton therapy. Patients with SCC had comprehensive treatment extending from the base of the skull to the clavicle. The dose for chemoradiation therapy and radiation therapy alone was 70 Gy and 66 Gy, respectively. The robustness of each treatment plan was also analyzed to evaluate sensitivity to uncertainties associated with variations in patient setup and the effect of uncertainties with proton beam range in patients. Proton beam energies during treatment ranged from 72.5 to 221.8 MeV. Spot sizes varied depending on the beam energy and depth of the target, and the scanning nozzle delivered the spot scanning treatment “spot-by-spot” and “layer-by-layer”
Results
Ten patients presented with squamous cell carcinoma (SCC) and 5 with adenoid cystic carcinoma (ACC). All 15 patients were able to complete treatment with MFO-IMPT with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths and with a median follow-up of 28 months (range: 20-35), the overall clinical complete response rate was 93.3% (95%, confidence interval 68.1% to 99.8%). Xerostomia occurred in all 15 patients as follows; Grade 1 - ten patients, Grade 2 - four patients, and Grade 3 - one patient. Mucositis within the planning target volumes was seen during the treatment of all patients; Grade 1 - one patient, Grade 2 - eight patients, and Grade 3 - six patients. No patient experienced Grade 2 or higher anterior oral mucositis.
Conclusions
This is the first clinical report of MFO-IMPT for head and neck tumors. Early clinical outcomes are encouraging and warrant further investigation of proton therapy in prospective clinical trials.
doi:10.1016/j.ijrobp.2014.04.019
PMCID: PMC4171724  PMID: 24867532
12.  Geometric interpretations for resonances of plasmonic nanoparticles 
Scientific Reports  2015;5:12148.
The field of plasmonics can be roughly categorized into two branches: surface plasmon polaritons (SPPs) propagating in waveguides and localized surface plasmons (LSPs) supported by scattering particles. Investigations along these two directions usually employ different approaches, resulting in more or less a dogma that the two branches progress almost independently of each other, with few interactions. Here in this work we interpret LSPs from a Bohr model based geometric perspective relying on SPPs, thus establishing a connection between these two sub-fields. Besides the clear explanations of conventional scattering features of plasmonic nanoparticles, based on this geometric model we further demonstrate other anomalous scattering features (higher order modes supported at lower frequencies, and blueshift of the resonance with increasing particle sizes) and multiple electric resonances of the same order supported at different frequencies, which have been revealed to originate from backward SPP modes and multiple dispersion bands supported in the corresponding plasmonic waveguides, respectively. Inspired by this geometric model, it is also shown that, through solely geometric tuning, the absorption of each LSP resonance can be maximized to reach the single channel absorption limit, provided that the scattering and absorption rates are tuned to be equal.
doi:10.1038/srep12148
PMCID: PMC4502409  PMID: 26173797
13.  Corneal Stroma Regeneration with Acellular Corneal Stroma Sheets and Keratocytes in a Rabbit Model 
PLoS ONE  2015;10(7):e0132705.
Acellular corneal stroma matrix has been used for corneal stroma engineering. However, because of its compact tissue structure, regrowth of keratocytes into the scaffold is difficult. Previously, we developed a sandwich model for cartilage engineering using acellular cartilage sheets. In the present study, we tested this model for corneal stroma regeneration using acellular porcine corneal stroma (APCS) sheets and keratocytes. Porcine corneas were decellularized by NaCl treatment, and the APCS was cut into 20-μm-thick sheets. A rabbit corneal stroma defect model was created by lamellar keratoplasty and repaired by transplantation of five pieces of APCS sheets with keratocytes. Six months after transplantation, transparent corneas were present in the experimental group, which were confirmed by anterior segment optical coherence tomography examination and transmittance examination. The biomechanical properties in the experimental group were similar to those of normal cornea. Histological analyses showed an even distribution of keratocytes and well-oriented matrix in the stroma layer in the experimental group. Together, these results demonstrated that the sandwich model using acellular corneal stroma sheets and keratocytes could be potentially useful for corneal stroma regeneration.
doi:10.1371/journal.pone.0132705
PMCID: PMC4500565  PMID: 26167895
14.  HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα 
Molecular cell  2014;55(1):31-46.
SUMMARY
MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.
doi:10.1016/j.molcel.2014.04.028
PMCID: PMC4188514  PMID: 24882211
15.  Effects of Helicobacter pylori Treatment on Gastric Cancer Incidence and Mortality in Subgroups 
Among 2258 Helicobacter pylori–seropositive subjects randomly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo, we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age, baseline gastric histopathology, and post-treatment infection status. We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses, respectively. Treatment was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36; 95% confidence interval [CI] = 0.17 to 0.79) and mortality (hazard ratio = 0.26; 95% CI = 0.09 to 0.79) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56; 95% CI = 0.34 to 0.91). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology, and benefits are present even with post-treatment infection, suggesting treatment can benefit an entire population, not just the young or those with mild histopathology.
doi:10.1093/jnci/dju116
PMCID: PMC4067110  PMID: 24925350
16.  Enteral Immunomodulatory Diet (Omega-3 Fatty Acid, γ-Linolenic Acid and Antioxidant Supplementation) for Acute Lung Injury and Acute Respiratory Distress Syndrome: An Updated Systematic Review and Meta-Analysis 
Nutrients  2015;7(7):5572-5585.
Enteral immunomodulatory nutrition is considered as a promising therapy for the treatment of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, there are still some divergences, and it is unclear whether this treatment should be recommended for patients with ALI/ARDS. Therefore, we conducted this systematic review and meta-analysis to assess the efficacy and safety of an enteral immunomodulatory diet on the clinical outcomes of ALI/ARDS patients. Methods: We retrieved potentially relevant clinical trials though electronic databases. All trials of enteral immunomodulatory diet for ALI/ARDS were included. Analyses of the overall all-cause mortality, 28-day ventilator-free days and 28-day intensive care unit (ICU) free days were conducted. Results: In total six controlled trials were evaluated. The pooled results did not show a significant reduction in the risk of all-cause mortality (M-H RR (the overall Mantel-Haenszel relative risk), 0.81 (95% CI, 0.50–1.31); p = 0.38; 6 trials, n = 717) in ALI/ARDS patients treated with the immunomodulatory diet. This treatment also did not extend the ventilator-free days and ICU-free days. However, patients with high mortality might benefit from this treatment. Conclusions: The enteral immunomodulatory diet could not reduce the severity of the patients with ALI/ARDS. Whereas, for ALI/ARDS patients with high mortality, this treatment might reduce the all-cause mortality, but its use should be treated with discretion.
doi:10.3390/nu7075239
PMCID: PMC4517016  PMID: 26184293
enteral nutrition; immunomodulatory diet; acute respiratory distress syndrome; acute lung injury; critical care; mortality
17.  A large cohort study of nonsteroidal anti-inflammatory drugs and renal cell carcinoma incidence in the National Institutes of Health–AARP Diet and Health Study 
Cancer causes & control : CCC  2013;24(10):1865-1873.
Aim
Existing epidemiologic evidence for the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and renal cell carcinoma (RCC) risk is inconsistent.
Methods
We investigated the association between the use of aspirin and nonaspirin NSAIDs and RCC risk in the National Institutes of Health–American Association of Retired Persons (AARP) Diet and Health Study, for which 298,468 AARP members free of cancer, aged 50–71 years, completed a survey on use of NSAIDs (1996–1997). Multivariate Cox proportional hazards models were used to estimate the hazard ratio (HR).
Results
The state cancer registry and mortality index linkage identified 1,084 incident RCC cases through 31 December 2006. No statistically significant associations between the use of aspirin or nonaspirin NSAIDs and RCC risk were found. Compared to nonuse of any NSAIDs, the multivariate-adjusted HRs were 0.95 (95 % CI 0.75–1.21) and 0.93 (95 % CI 0.68–1.26) for monthly use of aspirin and nonaspirin NSAIDs, respectively, 0.92 (95 % CI: 0.69-1.23) and 1.11 (95 % CI: 0.76-1.62) for weekly use, 0.87 (95 % CI: 0.69-1.11) and 1.06 (95 % CI: 0.75-1.48) for daily use; and 0.95 (95 % CI 0.78–1.14) for the use of both aspirin and nonaspirin NSAIDs. We found some suggestions of an increased risk of RCC associated with frequent NSAID use among participants who were <63 years and a reduced risk associated with aspirin use among those ≥63 years. No significant associations were found in other stratified analyses by gender, BMI, smoking, history of diabetes, or history of hypertension.
Conclusion
RCC risk was not significantly associated with NSAID use overall. The difference in association by age needs to be explored further.
doi:10.1007/s10552-013-0263-4
PMCID: PMC4486047  PMID: 23868221
Anti-inflammatory agents/nonsteroidal; Carcinoma/renal cell; NIH–AARP; Cohort studies
18.  Total Hepatitis B Core Antigen Antibody, a Quantitative Non-Invasive Marker of Hepatitis B Virus Induced Liver Disease 
PLoS ONE  2015;10(6):e0130209.
Non invasive immunologic markers of virus-induced liver disease are unmet needs. We tested the clinical significance of quantitative total and IgM-anti-HBc in well characterized chronic-HBsAg-carriers. Sera (212) were obtained from 111 HBsAg-carriers followed-up for 52 months (28-216) during different phases of chronic-HBV-genotype-D-infection: 10 HBeAg-positive, 25 inactive-carriers (HBV-DNA≤2000IU/ml, ALT<30U/L), 66 HBeAg-negative-CHB-patients and 10 with HDV-super-infection. In 35 patients treated with Peg-IFN±nucleos(t)ide-analogues (NUCs) sera were obtained at baseline, end-of-therapy and week-24-off-therapy and in 22 treated with NUCs (for 60 months, 42-134m) at baseline and end-of-follow-up. HBsAg and IgM-anti-HBc were measured by Architect-assays (Abbott, USA); total-anti-HBc by double-antigen-sandwich-immune-assay (Wantai, China); HBV-DNA by COBAS-TaqMan (Roche, Germany). Total-anti-HBc were detectable in all sera with lower levels in HBsAg-carriers without CHB (immune-tolerant, inactive and HDV-superinfected, median 3.26, range 2.26-4.49 Log10 IU/ml) versus untreated-CHB (median 4.68, range 2.76-5.54 Log10 IU/ml), p<0.0001. IgM-anti-HBc positive using the chronic-hepatitis-cut-off" (0.130-S/CO) were positive in 102 of 212 sera (48.1%). Overall total-anti-HBc and IgM-anti-HBc correlated significantly (p<0.001, r=0.417). Total-anti-HBc declined significantly in CHB patients with response to Peg-IFN (p<0.001) and in NUC-treated patients (p<0.001); the lowest levels (median 2.68, range 2.12-3.08 Log10 IU/ml) were found in long-term responders who cleared HBsAg subsequently. During spontaneous and therapy-induced fluctuations of CHB (remissions and reactivations) total- and IgM-anti-HBc correlated with ALT (p<0.001, r=0.351 and p=0.008, r=0.185 respectively). Total-anti-HBc qualifies as a useful marker of HBV-induced-liver-disease that might help to discriminate major phases of chronic HBV infection and to predict sustained response to antivirals.
doi:10.1371/journal.pone.0130209
PMCID: PMC4482637  PMID: 26115521
19.  Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition 
Cell stem cell  2013;13(2):237-245.
SUMMARY
DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and down-regulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain.
doi:10.1016/j.stem.2013.05.006
PMCID: PMC4474382  PMID: 23770080
20.  Analysis and Thoughts about the Negative Results of International Clinical Trials on Acupuncture 
An increasing number of randomized controlled trials (RCTs) of acupuncture have proved the clinical benefits of acupuncture; however, there are some results that have shown negative results or placebo effects. The paper carried out an in-depth analysis on 33 RCTs in the 2011 SCI database, the quality of the reports was judged according to Jadad scores, and the “Necessary Information Included in Reporting Interventions in Clinical Trials of Acupuncture (STRICTA 2010)” was taken as the standard to analyze the rationality of the therapeutic principle. The difference between the methodology (Jadad) scores of the two types of research reports did not constitute statistical significance (P > 0.05). The studies with negative results or placebo effects showed the following deficiencies with respect to intervention details: (1) incompletely rational acupoint selection; (2) inconsistent ability of acupuncturists; (3) negligible needling response to needling; (4) acupuncture treatment frequency too low in most studies; and (5) irrational setting of placebo control. Thus, the primary basis for the negative results or placebo effects of international clinical trials on acupuncture is not in the quality of the methodology, but in noncompliance with the essential requirements proposed by acupuncture theory in terms of clinical manipulation details.
doi:10.1155/2015/671242
PMCID: PMC4487698  PMID: 26161126
21.  Bone Morphogenetic Protein-9 Effectively Induces Osteo/Odontoblastic Differentiation of the Reversibly Immortalized Stem Cells of Dental Apical Papilla 
Stem Cells and Development  2014;23(12):1405-1416.
Dental pulp/dentin regeneration using dental stem cells combined with odontogenic factors may offer great promise to treat and/or prevent premature tooth loss. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing bone formation. Here, we investigate whether BMP9 can effectively induce odontogenic differentiation of the stem cells from mouse apical papilla (SCAPs). Using a reversible immortalization system expressing SV40 T flanked with Cre/loxP sites, we demonstrate that the SCAPs can be immortalized, resulting in immortalized SCAPs (iSCAPs) that express mesenchymal stem cell markers. BMP9 upregulates Runx2, Sox9, and PPARγ2 and odontoblastic markers, and induces alkaline phosphatase activity and matrix mineralization in the iSCAPs. Cre-mediated removal of SV40 T antigen decreases iSCAP proliferation. The in vivo stem cell implantation studies indicate that iSCAPs can differentiate into bone, cartilage, and, to lesser extent, adipocytes upon BMP9 stimulation. Our results demonstrate that the conditionally iSCAPs not only maintain long-term cell proliferation but also retain the ability to differentiate into multiple lineages, including osteo/odontoblastic differentiation. Thus, the reversibly iSCAPs may serve as an important tool to study SCAP biology and SCAP translational use in tooth engineering. Further, BMP9 may be explored as a novel and efficacious factor for odontogenic regeneration.
doi:10.1089/scd.2013.0580
PMCID: PMC4046201  PMID: 24517722
22.  Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives neoplastic transformation in NUT midline carcinoma 
Cancer research  2014;74(12):3332-3343.
BRD4 is implicated in the pathogenesis of a number of different cancers. It is also the target of translocation t(15;19) that accounts for the highly aggressive NUT midline carcinoma (NMC). We discovered that t(15;19) NMC cells display the ability to grow into stem cell-like spheres and express an exceptionally high level of the stem cell marker, SOX2. The BRD4-NUT fusion oncogene resulting from t(15;19) translocation is required for the abnormal activation of SOX2, which drives the stem cell-like proliferation and cellular transformation in NMC cells. SOX2 knockdown phenocopies the effects of BRD4-NUT inhibition, whereas ectopic SOX2 expression rescues the phenotype. The BRD4-NUT induced abnormal SOX2 activation was observed in multiple NMC cell lines as well as in NMC primary tumors. We further demonstrate that BRD4-NUT oncoprotein recruits p300 to stimulate transcription activation, and that inhibition of p300 represses SOX2 transcription in NMC cells. These studies identify this stem cell marker as a novel BRD4-NUT target that supports the highly aggressive transforming activity of t(15;19) carcinomas. Our study provides new mechanistic insights for understanding how alteration of BRD4 function by BRD4-NUT oncogene leads to the highly malignant NMC carcinoma. Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell-like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors.
doi:10.1158/0008-5472.CAN-13-2658
PMCID: PMC4097982  PMID: 24736545
BRD4 (bromodomain-containing protein 4); t(15;19) translocation; NUT Midline Carcinoma (NMC); BRD4-NUT fusion oncogene; stem cell marker SOX2; p300
23.  Interaction of Isophorone with Pd(111): A Combination of Infrared Reflection–Absorption Spectroscopy, Near-Edge X-ray Absorption Fine Structure, and Density Functional Theory Studies 
Atomistic level understanding of interaction of α,β-unsaturated carbonyls with late transition metals is a key prerequisite for rational design of new catalytic materials with the desired selectivity toward C=C or C=O bond hydrogenation. The interaction of this class of compounds with transition metals was investigated on α,β-unsaturated ketone isophorone on Pd(111) as a prototypical system. In this study, infrared reflection–absorption spectroscopy (IRAS), near-edge X-ray absorption fine structure (NEXAFS) experiments, and density functional theory calculations including van der Waals interactions (DFT+vdW) were combined to obtain detailed information on the binding of isophorone to palladium at different coverages and on the effect of preadsorbed hydrogen on the binding and adsorption geometry. According to these experimental observations and the results of theoretical calculations, isophorone adsorbs on Pd(111) in a flat-lying geometry at low coverages. With increasing coverage, both C=C and C=O bonds of isophorone tilt with respect to the surface plane. The tilting is considerably more pronounced for the C=C bond on the pristine Pd(111) surface, indicating a prominent perturbation and structural distortion of the conjugated π system upon interaction with Pd. Preadsorbed hydrogen leads to higher tilting angles of both π bonds, which points to much weaker interaction of isophorone with hydrogen-precovered Pd and suggests the conservation of the in-plane geometry of the conjugated π system. The results of the DFT+vdW calculations provide further insights into the perturbation of the molecular structure of isophorone on Pd(111).
doi:10.1021/jp506637v
PMCID: PMC4467905  PMID: 26089998
24.  Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude 
Critical Care  2015;19(1):255.
Introduction
Intracerebral hemorrhage (ICH) at high altitude is not well understood to date. This study investigates the effects of high altitude on ICH, and examines the acute neuroprotection of hyperbaric oxygen (HBO) therapy against high-altitude ICH.
Methods
Minipigs were placed in a hypobaric chamber for 72 h before the operation. ICH was induced by an infusion of autologous arterial blood (3 ml) into the right basal ganglia. Animals in the high-altitude ICH group received HBO therapy (2.5 ATA for 60 min) 30 min after ICH. Blood gas, blood glucose and brain tissue oxygen partial pressure (PbtO2) were monitored continuously for animals from all groups, as were microdialysis products including glucose, lactate, pyruvate and glutamate in perihematomal tissue from 3 to 12 h post-ICH.
Results
High-altitude ICH animals showed significantly lower PbtO2, higher lactate/pyruvate ratio (LPR) and glutamate levels than low-altitude ICH animals. More severe neurological deficits, brain edema and neuronal damage were also observed in high-altitude ICH. After HBO therapy, PbtO2 was significantly increased and LPR and glutamate levels were significantly decreased. Brain edema, neurological deficits and neuronal damage were also ameliorated.
Conclusions
The data suggested a more serious disturbance of tissue oxygenation and cerebral metabolism in the acute stage after ICH at high altitude. Early HBO treatment reduced acute brain injury, perhaps through a mechanism involving the amelioration of the derangement of cerebral oxygenation and metabolism following high-altitude ICH.
doi:10.1186/s13054-015-0976-8
PMCID: PMC4522125  PMID: 26073666

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