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1.  Differentiation of HIV-associated lymphoma from HIV-associated reactive adenopathy using quantitative FDG PET and symmetry 
Purpose
To determine the diagnostic accuracy of a semiautomated 18F-FDG PET/CT measurement of total lesion glycolysis (TLG), maximum and peak standardized uptake value at lean body mass (SUL-Max and SUL-Peak), qualitative estimates of left/right nodal symmetry and FDG uptake for differentiating lymphoma from reactive adenopathy in HIV-infected patients.
Methods
We retrospectively analyzed 41 whole-body 18F-FDG PET/CT studies performed in HIV-infected patients for clinical reasons. The study received institutional review board approval. Of the 41 patients, 19 had biopsy-proven untreated lymphoma, and 22 with reactive adenopathy without malignancy on follow-up were used as controls. Nodal and extranodal visual qualitative metabolic scores, SUL-Max, SUL-Peak, CT nodal size, and PERCIST 1.0 threshold-based TLG and metabolic tumor volume (MTV) were determined. The qualitative intensity of nodal involvement and symmetry of uptake were compared using receiver operator curve (ROC) analysis. HIV plasma viral RNA measurements were also obtained.
Results
All of the quantitative PET metrics performed well in differentiating lymphoma from reactive adenopathy and performed better than qualitative visual intensity scores. The areas under the ROC curves (AUC) were significantly higher for TLG=0.96, single SUL-Peak=0.96, single SUL-Max=0.97, and MTV=0.96, compared to 0.67 for CT nodal size (p<0.001). These PET metrics performed best in separating the two populations in aviremic patients, with AUCs of 1 (AUC 0.91 for CT nodal size). TLG, MTV, SUL-Peak and SUL-Max were more reliable markers among viremic individuals, with AUCs between 0.84 and 0.93, compared to other metrics. PET metrics were significantly correlated with plasma viral load in HIV-reactive adenopathy controls. Asymmetrical FDG uptake had an accuracy of 90.4 % for differentiating lymphoma from reactive adenopathy in HIV-infected patients.
Conclusion
Quantitative PET metabolic metrics as well as the qualitative assessment of symmetry of nodal uptake appear to be valuable tools for differentiating lymphoma from reactive adenopathy in HIV-infected patients using FDG PET. These parameters appear more robust in aviremic patients.
doi:10.1007/s00259-013-2671-9
PMCID: PMC4322908  PMID: 24469258
PET/CT; HIV; Lymphoma; Lymphadenopathy; TLG
2.  18F-FDG PET of the hands with a dedicated high-resolution PEM system (arthro-PET): correlation with PET/CT, radiography and clinical parameters 
Purpose
The aim of this study was to prospectively determine the feasibility and compare the novel use of a positron emission mammography (PEM) scanner with standard PET/CT for evaluating hand osteoarthritis (OA) with 18F-FDG.
Methods
Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study in which 14 adults referred for oncological 18F-FDG PET/CT underwent dedicated hand PET/CT followed by arthro-PET using the PEM device. Hand radiographs were obtained and scored for the presence and severity of OA. Summed qualitative and quantitative joint glycolytic scores for each modality were compared with the findings on plain radiography and clinical features.
Results
Eight patients with clinical and/or radiographic evidence of OA comprised the OA group (mean age 73±7.7 years). Six patients served as the control group (53.7±9.3 years). Arthro-PET quantitative and qualitative joint glycolytic scores were highly correlated with PET/CT findings in the OA patients (r=0.86. p =0.007; r=0.94, p=0.001). Qualitative arthro-PET and PET/CT joint scores were significantly higher in the OA patients than in controls (38.7±6.6 vs. 32.2±0.4, p=0.02; 37.5±5.4 vs. 32.2±0.4, p=0.03, respectively). Quantitative arthro-PET and PET/CT maximum SUV-lean joint scores were higher in the OA patients, although they did not reach statistical significance (20.8±4.2 vs. 18±1.8, p= 0.13; 22.8±5.38 vs. 20.1±1.54, p=0.21). By definition, OA patients had higher radiographic joint scores than controls (30.9±31.3 vs. 0, p=0.03).
Conclusion
Hand imaging using a small field of view PEM system (arthro-PET) with FDG is feasible, performing comparably to PET/CT in assessing metabolic joint activity. Arthro-PET and PET/CT showed higher joint FDG uptake in OA. Further exploration of arthro-PET in arthritis management is warranted.
doi:10.1007/s00259-014-2856-x
PMCID: PMC4322913  PMID: 25134669
PET/CT; Positron emission mammography (PEM); Osteoarthritis (OA); Arthritis; 18F-Fluoro- 2-deoxy-D-glucose (FDG)
3.  Saliva and Plasma Quantitative Polymerase Chain Reaction–Based Detection and Surveillance of Human Papillomavirus–Related Head and Neck Cancer 
IMPORTANCE
Human papillomavirus type 16 (HPV-16) is a major causative factor in oropharyngeal squamous cell carcinoma (OPSCC). The detection of primary OPSCC is often delayed owing to the challenging anatomy of the oropharynx.
OBJECTIVE
To investigate the feasibility of HPV-16 DNA detection in pretreatment and posttreatment plasma and saliva and its potential role as a marker of prognosis.
DESIGN, SETTING, AND PARTICIPANTS
This is a retrospective analysis of a prospectively collected cohort. Among a cohort of patients with oropharyngeal and unknown primary squamous cell carcinoma with known HPV-16 tumor status from the Johns Hopkins Medical Institutions and Greater Baltimore Medical Center (from 1999 through 2010), 93 patients were identified with a complete set of pretreatment and posttreatment plasma or saliva samples, of which 81 patients had HPV-16–positive tumors and 12 patients had HPV-16–negative tumors. Real-time quantitative polymerase chain reaction was used to detect HPV-16 E6 and E7 DNA in saliva and plasma samples.
MAIN OUTCOMES AND MEASURES
Main outcomes included sensitivity, specificity, negative predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status, as well as the association of posttreatment HPV DNA status with clinical outcomes, including recurrence-free survival and overall survival.
RESULTS
The median follow-up time was 49 months (range, 0.9–181.0 months). The sensitivity, specificity, negative predictive value, and positive predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status were 76%, 100%, 42%, and 100%, respectively. The sensitivities of pretreatment saliva or plasma alone were 52.8%and 67.3%, respectively. In a multivariable analysis, positive posttreatment saliva HPV status was associated with higher risk of recurrence (hazard ratio [HR], 10.7; 95% CI, 2.36–48.50) (P = .002). Overall survival was reduced among those with posttreatment HPV-positive status in saliva (HR, 25.9; 95% CI, 3.23–208.00) (P = .002) and those with HPV-positive status in either saliva or plasma but not among patients with HPV-positive status in plasma alone. The combined saliva and plasma posttreatment HPV-16 DNA status was 90.7%specific and 69.5%sensitive in predicting recurrence within 3 years.
CONCLUSIONS AND RELEVANCE
Using a combination of pretreatment plasma and saliva can increase the sensitivity of pretreatment HPV-16 status as a tool for screening patients with HPV-16–positive OPSCC. In addition, analysis of HPV-16 DNA in saliva and plasma after primary treatment may allow for early detection of recurrence in patients with HPV-16–positive OPSCC.
doi:10.1001/jamaoto.2014.1338
PMCID: PMC4313904  PMID: 25078109
4.  MiR-203 down-regulates Rap1A and suppresses cell proliferation, adhesion and invasion in prostate cancer 
Objective
Evidence supports an important role for miR-203 in the regulation of the proliferation, migration and invasion of prostate cancer (PCa) cells. However, the exact mechanisms of miR-203 in PCa are not entirely clear.
Methods
We examined the expression of miR-203 in prostate cancer tissues, adjacent normal tissues, PCa cell lines and normal prostate epithelial cells by qRT-PCR. Then, the effects of miR-203 or Rap1A on proliferation, adhesion and invasion of PCa cells were assayed using CKK-8, adhesion analysis, and transwell invasion assays. Luciferase reporter assay was performed to assess miR-203 binding to Rap1A mRNA. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice.
Results
Here, we confirmed that the expression of miR-203 was significantly downregulated in prostate cancer specimens compared with matched adjacent normal prostate specimens. Mechanistic dissection revealed that miR-203 mediated cell proliferation, adhesion and invasion in vitro, and tumor growth in vivo, as evidenced by reduced RAC1, p-PAK1, and p-MEK1 expression. In addition, we identified Rap1A as a direct target suppressed by miR-203, and there was an inverse relationship between the expression of miR-203 and Rap1A in PCa. Knockdown of Rap1A phenocopied the effects of miR-203 on PCa cell growth and invasion. Furthermore, Rap1A over-expression in PCa cells partially reversed the effects of miR-203-expression on cell adhesion and invasion.
Conclusions
These findings provide further evidence that a crucial role for miR-203 in inhibiting metastasis of PCa through the suppression of Rap1A expression.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0125-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-015-0125-x
PMCID: PMC4321708  PMID: 25636908
miR-203; Prostate cancer; Rap1A; Cell proliferation; Cell adhesion; Cell invasion
5.  Type II transmembrane domain hydrophobicity dictates the cotranslational dependence for inversion 
Molecular Biology of the Cell  2014;25(21):3363-3374.
The cellular hydrophobicity threshold for the inversion of Sec-dependent Nin-Cout (type II) transmembrane domains is dictated by whether their membrane integration occurs cotranslationally or posttranslationally.
Membrane insertion by the Sec61 translocon in the endoplasmic reticulum (ER) is highly dependent on hydrophobicity. This places stringent hydrophobicity requirements on transmembrane domains (TMDs) from single-spanning membrane proteins. On examining the single-spanning influenza A membrane proteins, we found that the strict hydrophobicity requirement applies to the Nout-Cin HA and M2 TMDs but not the Nin-Cout TMDs from the type II membrane protein neuraminidase (NA). To investigate this discrepancy, we analyzed NA TMDs of varying hydrophobicity, followed by increasing polypeptide lengths, in mammalian cells and ER microsomes. Our results show that the marginally hydrophobic NA TMDs (ΔGapp > 0 kcal/mol) require the cotranslational insertion process for facilitating their inversion during translocation and a positively charged N-terminal flanking residue and that NA inversion enhances its plasma membrane localization. Overall the cotranslational inversion of marginally hydrophobic NA TMDs initiates once ∼70 amino acids past the TMD are synthesized, and the efficiency reaches 50% by ∼100 amino acids, consistent with the positioning of this TMD class in type II human membrane proteins. Inversion of the M2 TMD, achieved by elongating its C-terminus, underscores the contribution of cotranslational synthesis to TMD inversion.
doi:10.1091/mbc.E14-04-0874
PMCID: PMC4214783  PMID: 25165139
6.  Efficient Transduction of LEDGF/p75 Mutant Cells by Gain-of-Function HIV-1 Integrase Mutant Viruses 
Controlling the specificity of retroviral DNA integration could improve the safety of gene therapy vectors, and fusions of heterologous chromatin binding modules to the integrase-binding domain from the lentiviral integration host cofactor LEDGF/p75 are a promising retargeting strategy. We previously proposed the utility of integrase mutant lentiviral vectors that are selectively activated by complementary LEDGF/p75 variants, and our initial modifications in HIV-1 integrase and LEDGF/p75 supported about 13% of wild-type vector transduction activity. Here we describe the selection and characterization of the K42E gain-of-function mutation in HIV-1 integrase, which greatly improves the efficiency of this system. Both K42E and initial reverse-charge mutations in integrase negatively impacted reverse transcription and integration, yet when combined together boosted viral transduction efficiency to ~75% of the wild-type vector in a manner dependent on a complementary LEDGF/p75 variant. Although the K42E mutation conferred functional gains to integrase mutant viral reverse transcription and integration, only the integration boost depended on the engineered LEDGF/p75 mutant. We conclude that the specificity of lentiviral retargeting strategies based on heterologous LEDGF/p75 fusion proteins will benefit from our optimized system that utilizes the unique complementation properties of reverse-charge integrase mutant viral and LEDGF/p75 host proteins.
doi:10.1038/mtm.2013.2
PMCID: PMC4222252  PMID: 25383358
7.  Identifying pediatric cancer clusters in Florida using loglinear models and generalized lasso penalties 
We discuss the identification of pediatric cancer clusters in Florida between 2000 and 2010 using a penalized generalized linear model. More specifically, we introduce a Poisson model for the observed number of cases on each of Florida's ZIP Code Tabulation Areas (ZCTA) and regularize the associated disease rate estimates using a generalized Lasso penalty. Our analysis suggests the presence of a number of pediatric cancer clusters during the period over study, with the largest ones being located around the cities of Jacksonville, Miami, Cape Coral/Fort Meyers and Palm Beach.
doi:10.1080/2330443X.2014.960120
PMCID: PMC4280570  PMID: 25558468
Loglinear Models; Generalized Lasso; Poisson Regression; Disease Clustering; Pediatric Cancer
9.  Impairment of Myocardial Mitochondria in Viral Myocardial Disease and Its Reflective Window in Peripheral Cells 
PLoS ONE  2014;9(12):e116239.
Background
Viral myocardial disease (VMD) is a common disease inducing heart failure. It has not been clear the roles of mitochondrial damage in the pathological changes of cardiomyocytes in VMD.
Methods
Myocardial tissues and lymphocytes were collected from 83 VMD patients. Control groups included 12 cases of healthy accidental death with myocardial autopsy and 23 healthy blood donors. The mouse model of viral myocarditis (VMC) was established by Coxsackie virus B3 infection and myocardial tissues and skeletal muscle were collected. Mitochondrial DNA (mtDNA) deletion rate was quantitatively determined using polymerase chain reaction.
Results
There was significantly difference of myocardial mitochondrial DNA deletion rate between VMD or VMC group and control group (P<0.05). Moreover, the loss of mitochondrial membrane phospholipids was significantly different between VMD or VMC group and control group. In VMC mice, there were negative correlations between myocardial mtDNA3867 deletion rate and left ventricular peak systolic pressure (LVPSP) (r = −0.66, P<0.05), and between myocardial mtDNA3867 deletion rate and +dp/dtmax (r = −0.79, P<0.05), while there was positive correlation between myocardial mtDNA3867 deletion rate and −dp/dtmax (r = 0.80, P<0.05).
Conclusion
Mitochondrial damage is an important pathophysiological mechanism leading to myocardial injury and cardiac dysfunction. The mitochondrial damage in the skeletal muscle and lymphocytes reflect a “window” of myocardial mitochondrial damage.
doi:10.1371/journal.pone.0116239
PMCID: PMC4281208  PMID: 25551390
10.  Blastic plasmacytoid dendritic cell neoplasm: A case report 
Oncology Letters  2014;9(3):1388-1392.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), formerly known as agranular cluster of differentiation (CD)4+/CD56+ hematodermic neoplasm, is a rare and aggressive type of lymphoma, with only ~100 cases reported worldwide. BPDCN is a hematological malignancy derived from precursors of plasmacytoid dendritic cells and is clinically characterized by cutaneous manifestations involving the lymph nodes and peripheral blood, a leukemia-like dissemination and a poor prognosis. The present study reports the case of a 54-year-old male who presented with symptoms characteristic of BPDCN. Pathological and immunohistochemical analysis of abdominal skin lesion biopsies were used to determine a diagnosis of stage IIIE BPDCN. Although cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy was administered, the patient succumbed to BPDCN nine days after the discontinuation of chemotherapy. Thus, the period from BPDCN presentation to mortality was ≤3 months. The case reported in the present study was characterized by rapid development and poor prognosis, and displayed additional features of BPDCN, including systemic dissemination and a short survival period.
doi:10.3892/ol.2014.2836
PMCID: PMC4314974  PMID: 25663917
blastic plasmacytoid dendritic cell neoplasm; cyclophosphamide; doxorubicin; vincristine and prednisolone chemotherapy; prognosis; treatment; diagnosis
11.  CT-guidance interstitial 125Iodine seed brachytherapy as a salvage therapy for recurrent spinal primary tumors 
Background
Management of spinal neoplasms has relied on open surgery and external beam radiotherapy (EBRT). Although primary spinal tumors are rare, their treatment remains a pervasive problem. This analysis sought to evaluate the safety and efficacy of CT-guided 125I seed brachytherapy for recurrent paraspinous and vertebral primary tumors.
Methods
From November 2002 to June 2014, 17 patients who met the inclusion criteria were retrospectively reviewed. 14 (82.4%) had previously undergone surgery, 15 (88.2%) had received conventional EBRT and 3 (17.6%) had chosen chemotherapy. The number of 125I seeds implanted ranged from 7 to 122 (median 79) with specific activity of 0.5-0.8 mCi (median 0.7 mCi). The post-plan showed that the actuarial D90 of 125I seeds were 90–183 Gy (median 137 Gy). The follow-up period ranged from 2 to 69 months (median 19 months). The local control rate was calculated by the Kaplan-Meier method.
Results
For 5 Chondrosarcomas, the 1-, 2-, 3-year local control rates were 75%, 37.5%, and 37.5%, respectively, with a median of 34 months (range, 4–39 months). For 4 chordomas, the local control rate was 50% with a median follow-up of 13 months (range, 3–17 months). For 3 fibromatosis, all of them were survival without local recurrence at the end of follow-up. During the follow-up period, 35.3% (6/17) died from metastases, 17.6% (3/17) developed local recurrence by 8, 14 and 34 months while 64.7% (11/17) remained alive. 100% experienced pain relief and normal or improved ambulation, without more than Frankel grade 3 radiation myelopathy.
Conclusions
Percutaneous 125I seed implantation can be an alternative or retreatment for recurrent spinal primary tumors.
doi:10.1186/s13014-014-0301-8
PMCID: PMC4299295  PMID: 25534142
Brachytherapy; 125I seed implantation; Primary spine tumors; CT-guided; Outcome
12.  Preparation and Characterization of Gelatin-Based Mucoadhesive Nanocomposites as Intravesical Gene Delivery Scaffolds 
BioMed Research International  2014;2014:473823.
This study aimed to develop optimal gelatin-based mucoadhesive nanocomposites as scaffolds for intravesical gene delivery to the urothelium. Hydrogels were prepared by chemically crosslinking gelatin A or B with glutaraldehyde. Physicochemical and delivery properties including hydration ratio, viscosity, size, yield, thermosensitivity, and enzymatic degradation were studied, and scanning electron microscopy (SEM) was carried out. The optimal hydrogels (H), composed of 15% gelatin A175, displayed an 81.5% yield rate, 87.1% hydration ratio, 42.9 Pa·s viscosity, and 125.8 nm particle size. The crosslinking density of the hydrogels was determined by performing pronase degradation and ninhydrin assays. In vitro lentivirus (LV) release studies involving p24 capsid protein analysis in 293T cells revealed that hydrogels containing lentivirus (H-LV) had a higher cumulative release than that observed for LV alone (3.7-, 2.3-, and 2.3-fold at days 1, 3, and 5, resp.). Lentivirus from lentivector constructed green fluorescent protein (GFP) was then entrapped in hydrogels (H-LV-GFP). H-LV-GFP showed enhanced gene delivery in AY-27 cells in vitro and to rat urothelium by intravesical instillation in vivo. Cystometrogram showed mucoadhesive H-LV reduced peak micturition and threshold pressure and increased bladder compliance. In this study, we successfully developed first optimal gelatin-based mucoadhesive nanocomposites as intravesical gene delivery scaffolds.
doi:10.1155/2014/473823
PMCID: PMC4279131  PMID: 25580433
13.  Reduced mir-29b-3p expression up-regulate CDK6 and contributes to IgA nephropathy 
IgA nephropathy (IgAN) is the most common glomerulonephritis and the etiology of which is complex and multiple, and the pathological damage of IgAN is diversified. MicroRNA is a kind of gene expression suppressor and recently, researchers have found that microRNAs may play an important role in the pathogenesis of IgAN. Herein, we found that miR-29b-3p not miR-29a or miR-29c was significantly down regulated in IgAN patients’ renal tissues. Predicted by bioinformatics tools and confirmed by dual luciferase assay and western blot, we found that the expression of CDK6 was repressed by miR-29b-3p directly. Subsequently, we found that miR-29b-3p down-regulation caused CDK6 overexpression can promote NF-κB signal by phosphorylating p65 which may enhance inflammation during IgAN pathogenesis.
PMCID: PMC4307478  PMID: 25664031
MicroRNA; IgA nephropathy; CDK6; p65; phosphorylation
14.  Plasma mRNA expression levels of BRCA1 and TS as potential predictive biomarkers for chemotherapy in gastric cancer 
Objective
Personalized chemotherapy based on predictive biomarkers can maximize efficacy. However, tumor tissue obtained at the time of initial diagnosis will not reflect genetic alterations observed at the time of disease progression. We have examined whether plasma mRNA levels can be a surrogate for tumor levels in predicting chemosensitivity.
Methods
In 150 gastric cancer patients, mRNA levels of BRCA1 and TS were assessed in plasma and paired tumor tissue. The Mann-Whitney U-test was used to compare mRNA expression levels between tumor samples exhibiting in vitro sensitivity or resistance to docetaxel and pemetrexed. All statistical tests were two-sided.
Results
There were significant correlations between plasma and tumor mRNA levels of BRCA1 (rho = 0.696, P < 0.001) and TS (rho = 0.620, P < 0.001). BRCA1 levels in plasma (docetaxel-sensitive: 1.25; docetaxel-resistant: 0.50, P < 0.001) and tumor (docetaxel-sensitive: 8.81; docetaxel-resistant: 4.88, P < 0.001) were positively associated with docetaxel sensitivity. TS levels in plasma (pemetrexed-sensitive: 0.90; pemetrexed-resistant: 1.82, P < 0.001) and tumor (pemetrexed-sensitive: 6.56; pemetrexed-resistant: 16.69, P < 0.001) were negatively associated with pemetrexed sensitivity.
Conclusions
Plasma mRNA expression levels mirror those in the tumor and may have a promising role as potential predictive biomarkers for chemotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0355-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0355-2
PMCID: PMC4302091  PMID: 25496700
Plasma mRNA; Gastric cancer; Chemosensitivity; Predictive biomarker; HDRA
15.  Roles of Caloric Restriction, Ketogenic Diet and Intermittent Fasting during Initiation, Progression and Metastasis of Cancer in Animal Models: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(12):e115147.
Background
The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies.
Methods
Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction.
Results
Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI) of 0.20 (0.12, 0.34) relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer.
Conclusions
Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated.
doi:10.1371/journal.pone.0115147
PMCID: PMC4263749  PMID: 25502434
16.  Fractional Exhaled Nitric Oxide in Healthy Tibetans at High Altitude 
Background
Fractional exhaled NO (FENO) is a marker of airway inflammation. For successful use of this marker it is important to have reference ranges from different healthy populations. The aim of this study was to establish these in healthy Tibetan adults who had always lived at high altitude on the Qinghai-Tibet Plateau.
Materia/Methods
The study included 145 healthy Tibetan subjects, aged 18 to 75 years, who were non-smokers. FENO was measured at a flow rate of 50 mL/s using a chemiluminescence analyzer. Residential altitude was classified as: Grade 1 (3678–3800 m), Grade 2 (3800–4200 m), or Grade 3 (>4200 m). Correlations between subject characteristics (age, sex, height, and weight), altitude, and FENO were investigated.
Results
The geometric mean FENO (95% CI) was 15.4 (7.0, 35.0) parts per billion (ppb). The 95% upper limit of the log-transformed data was 33.0 ppb, which was slightly lower than that for Han Chinese, and much lower than in the Northwest Han population. Mean FENO values were higher in males (16.8 ppb) than females (14.3 ppb) and inversely related to altitude. Multiple linear regression analysis showed that FENO was predicted by the equation Ln (FENO)=[2.844+0.161 × sex (1 for male; 0 for female) −0.111 × altitude grade]. The residual standard deviation (SD) was 0.048, and the explanatory value was 7%.
Conclusions
The upper limit of FENO in healthy Tibetan adults is 33 ppb. This value can be predicted on the basis of sex and altitude.
doi:10.12659/MSM.891369
PMCID: PMC4266363  PMID: 25481354
Altitude Sickness; Nitric Oxide Synthase Type III; Tibet
17.  Optical coherence tomography – near infrared spectroscopy system and catheter for intravascular imaging 
Optics Express  2013;21(25):30849-30858.
Owing to its superior resolution, intravascular optical coherence tomography (IVOCT) is a promising tool for imaging the microstructure of coronary artery walls. However, IVOCT does not identify chemicals and molecules in the tissue, which is required for a more complete understanding and accurate diagnosis of coronary disease. Here we present a dual-modality imaging system and catheter that uniquely combines IVOCT with diffuse near-infrared spectroscopy (NIRS) in a single dual-modality imaging device for simultaneous acquisition of microstructural and compositional information. As a proof-of-concept demonstration, the device has been used to visualize co-incident microstructural and spectroscopic information obtained from a diseased cadaver human coronary artery.
doi:10.1364/OE.21.030849
PMCID: PMC3926541  PMID: 24514658
(110.4500) Optical coherence tomography; (170.6510) Spectroscopy, tissue diagnostics; (110.0113) Imaging through turbid media
18.  Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice 
Background
Endometrial regenerative cells (ERCs) are mesenchymal-like stem cells that can be non-invasively obtained from menstrual blood and are easily grown /generated at a large scale without tumorigenesis. We previously reported that ERCs exhibit unique immunoregulatory properties in vitro, however their immunosuppressive potential in protecting the colon from colitis has not been investigated. The present study was undertaken to determine the efficacy of ERCs in mediating immunomodulatory functions against colitis.
Methods
Colitis was induced by 4% dextran-sulfate-sodium (DSS, in drinking water) in BALB/c mice for 7 days. ERCs were cultured from healthy female menstrual blood, and injected (1 million/mouse/day, i.v.) into mice on days 2, 5, and 8 following colitis induction. Colonic and splenic tissues were collected on day 14 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated.
Results
DSS-induced mice in untreated group developed severe colitis, characterized by body-weight loss, bloody stool, diarrhea, mucosal ulceration and colon shortening, as well as pathological changes of intra-colon cell infiltrations of neutrophils and Mac-1 positive cells. Notably, ERCs attenuated colitis with significantly reduced DAI, decreased levels of intra-colon IL-2 and TNF-α, but increased expressions of IL-4 and IL-10. Compared with those of untreated colitis mice, splenic dendritic cells isolated from ERC-treated mice exhibited significantly decreased MHC-II expression. ERC-treated mice also demonstrated much less CD3+CD25+ active T cell and CD3+CD8+ T cell population and significantly higher level of CD4+CD25+Foxp3+ Treg cells.
Conclusions
This study demonstrated novel anti-inflammatory and immunosuppressive effects of ERCs in attenuating colitis in mice, and suggested that the unique features of ERCs make them a promising therapeutic tool for the treatment of ulcerative colitis.
doi:10.1186/s12967-014-0344-5
PMCID: PMC4269937  PMID: 25475342
Endometrial regenerative cells; Colitis; Mice
19.  Recurrent Loss of Specific Introns during Angiosperm Evolution 
PLoS Genetics  2014;10(12):e1004843.
Numerous instances of presence/absence variations for introns have been documented in eukaryotes, and some cases of recurrent loss of the same intron have been suggested. However, there has been no comprehensive or phylogenetically deep analysis of recurrent intron loss. Of 883 cases of intron presence/absence variation that we detected in five sequenced grass genomes, 93 were confirmed as recurrent losses and the rest could be explained by single losses (652) or single gains (118). No case of recurrent intron gain was observed. Deep phylogenetic analysis often indicated that apparent intron gains were actually numerous independent losses of the same intron. Recurrent loss exhibited extreme non-randomness, in that some introns were removed independently in many lineages. The two larger genomes, maize and sorghum, were found to have a higher rate of both recurrent loss and overall loss and/or gain than foxtail millet, rice or Brachypodium. Adjacent introns and small introns were found to be preferentially lost. Intron loss genes exhibited a high frequency of germ line or early embryogenesis expression. In addition, flanking exon A+T-richness and intron TG/CG ratios were higher in retained introns. This last result suggests that epigenetic status, as evidenced by a loss of methylated CG dinucleotides, may play a role in the process of intron loss. This study provides the first comprehensive analysis of recurrent intron loss, makes a series of novel findings on the patterns of recurrent intron loss during the evolution of the grass family, and provides insight into the molecular mechanism(s) underlying intron loss.
Author Summary
The spliceosomal introns are nucleotide sequences that interrupt coding regions of eukaryotic genes and are removed by RNA splicing after transcription. Recent studies have reported several examples of possible recurrent intron loss or gain, i.e., introns that are independently removed from or inserted into the identical sites more than once in an investigated phylogeny. However, the frequency, evolutionary patterns or other characteristics of recurrent intron turnover remain unknown. We provide results for the first comprehensive analysis of recurrent intron turnover within a plant family and show that recurrent intron loss represents a considerable portion of all intron losses identified and intron loss events far outnumber intron gain events. We also demonstrate that recurrent intron loss is non-random, affecting only a small number of introns that are repeatedly lost, and that different lineages show significantly different rates of intron loss. Our results suggest a possible role of DNA methylation in the process of intron loss. Moreover, this study provides strong support for the model of intron loss by reverse transcriptase mediated conversion of genes by their processed mRNA transcripts.
doi:10.1371/journal.pgen.1004843
PMCID: PMC4256211  PMID: 25474210
20.  Simultaneous determination of multiple amino acids in plasma in critical illness by high performance liquid chromatography with ultraviolet and fluorescence detection 
There is increasing recognition that the host response to critical illness includes derangement of multiple amino acid pathways, including amino acids (AAs) central to metabolism and immune, endothelial and neurological function. To characterise concentration changes of these plasma amino acid we report the development and validation of a method for the quantification of AAs in small volumes of plasma (50 μL) using HPLC with simultaneous UV and fluorescence (FL) detection. Protein precipitation and pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) is followed by reversed phase HPLC separation. Calibration curves were built with norleucine as an internal standard. Thirty three (including the 20 proteinogenic) AAs, were selected as standards and their corresponding concentrations in the plasma of healthy human controls and patients with severe falciparum malaria were quantified. This method enables the detection of perturbations in arginine metabolism, aromatic amino acid pathways, methionine transsulfuration and transmethylation pathways and other metabolic pathways.
doi:10.1016/j.jchromb.2013.09.016
PMCID: PMC3855568  PMID: 24145014
Amino acids; malaria; critical illness; HPLC
21.  Uniportal video assisted thoracoscopic lobectomy: primary experience from an Eastern center 
Journal of Thoracic Disease  2014;6(12):1751-1756.
Background
Uniportal video-assisted thoracoscopic surgery (VATS) lobectomy is an emerging technique for the surgical resection of non-small cell lung cancer (NSCLC). Besides its wide debates on safety and efficacy throughout the world, there were few report on uniportal VATS from the Eastern countries. In this article, we summarized our primary experience on uniportal VATS lobectomy in an Eastern center.
Methods
From October 2013 till February 2014, 54 consecutive uniportal VATS lobectomy were performed in the Department of Thoracic Surgery, Zhongshan Hospital of Fudan University. Patients’ clinical features and operative details were recorded. Post-operatively, the morbidity and mortality were recorded to analyze the safety and efficacy of uniportal VATS lobectomy for NSCLCs.
Results
Among the 54 planned uniportal VATS lobectomy, there was one conversion to mini-thoracotomy due to lymph node sticking. Extra ports were required in two patients. The uniportal VATS lobectomy was achieved in 51 out of 54 patients (94.4%). The average operation duration was 122.2±37.5 min (90-160 min). The average volume of estimated blood loss during the operation was 88.8±47.1 mL (50-200 mL). The mean chest tube duration and hospital stay were 3.2±1.9 days and 4.6±2.0 days, respectively. There was no postoperative mortality in this study. Two patients suffered from prolonged air leakage (5 and 7 days), and one atrial fibrillation was observed in this cohort.
Conclusions
Based on our primary experience, uniportal VATS lobectomy is a safe and effective procedure for the surgical resection of NSCLCs. The surgical refinements and instrumental improvements would facilitate the technique. Further studies based on larger population are required to determine its benefits towards patients with NSCLCs.
doi:10.3978/j.issn.2072-1439.2014.11.20
PMCID: PMC4283325  PMID: 25589969
Lobectomy; minimally invasive surgery; non-small-cell-lung carcinoma (NSCLC)
22.  Non-antibiotic quorum sensing inhibitors acting against N-acyl homoserine lactone synthase as druggable target 
Scientific Reports  2014;4:7245.
N-acylhomoserine lactone (AHL)-based quorum sensing (QS) is important for the regulation of proteobacterial virulence determinants. Thus, the inhibition of AHL synthases offers non-antibiotics-based therapeutic potentials against QS-mediated bacterial infections. In this work, functional AHL synthases of Pseudomonas aeruginosa LasI and RhlI were heterologously expressed in an AHL-negative Escherichia coli followed by assessments on their AHLs production using AHL biosensors and high resolution liquid chromatography–mass spectrometry (LCMS). These AHL-producing E. coli served as tools for screening AHL synthase inhibitors. Based on a campaign of screening synthetic molecules and natural products using our approach, three strongest inhibitors namely are salicylic acid, tannic acid and trans-cinnamaldehyde have been identified. LCMS analysis further confirmed tannic acid and trans-cinnemaldehyde efficiently inhibited AHL production by RhlI. We further demonstrated the application of trans-cinnemaldehyde inhibiting Rhl QS system regulated pyocyanin production in P. aeruginosa up to 42.06%. Molecular docking analysis suggested that trans-cinnemaldehyde binds to the LasI and EsaI with known structures mainly interacting with their substrate binding sites. Our data suggested a new class of QS-inhibiting agents from natural products targeting AHL synthase and provided a potential approach for facilitating the discovery of anti-QS signal synthesis as basis of novel anti-infective approach.
doi:10.1038/srep07245
PMCID: PMC4246208  PMID: 25430794
23.  The Effect of Lateral Decubitus Position on Nocturnal Intraocular Pressure over a Habitual 24-Hour Period in Healthy Adults 
PLoS ONE  2014;9(11):e113590.
Purpose
To investigate the effect of lateral decubitus position (LDP) on nocturnal intraocular pressure (IOP) and the effect of LDP on 24-hour habitual IOP pattern in healthy subjects.
Methods
Intraocular pressure was measured every 2-hours using an Accupen Applanation Tonometer (Accutome, USA). During the diurnal period (7:30 am, 9:30 am, 11:30 am, 1:30 pm, 3:30 pm, 5:30 pm, 7:30 pm, and 9:30 pm), IOP was measured in the sitting position under bright light (500–1000 lux) after the subjects had been seated for 5 min. The nocturnal IOP was measured in the supine position, right LDP, and left LDP, with randomized sequences, under dim light (<10 lux) at 11:30 pm, 1:30 am, 3:30 am, and 5:30 am. The subjects were awakened and maintained each position for 5 min before the measurement. The 24-hour habitual IOP patterns were obtained according to the nocturnal position (supine, right LDP and left LDP) for either eye. P<0.05 was considered to be significant.
Results
Nineteen healthy subjects were included with a mean age of 51.3±5.8 years. During the nocturnal period, a significant IOP difference was found between the dependent eye (the eye on the lower side) of LDP and the supine position, but not for all the nocturnal time points. Over a 24-hour period, the effect of LDP on habitual IOP pattern was not statistically significant, although the mean nocturnal IOP and the diurnal-nocturnal IOP change for the right and the left eye in the LDP pattern was slightly higher than that in the sitting-supine pattern.
Conclusion
Significant nocturnal IOP differences existed between the dependent eye and the supine, but did not occur consistently for all time points. Over a 24-hour period, the effect of LDP on habitual IOP pattern was not statistically significant in healthy subjects.
doi:10.1371/journal.pone.0113590
PMCID: PMC4244118  PMID: 25423190
24.  The epidemiology, antifungal use and risk factors of death in elderly patients with candidemia: a multicentre retrospective study 
BMC Infectious Diseases  2014;14(1):609.
Background
The elderly patients affected by candidemia are growing in proportion to inpatients, but available data are limited. We aimed to determine the epidemiology, antifungal management and clinical risk factors of death in the elderly population with candidemia in China.
Methods
This retrospective study included 63 elderly (≥65 years) and 84 younger patients (16–60 years) at 4 tertiary hospitals. Multivariable logistic regression model was used to identify independent risk factors of death in elderly patients.
Results
The distribution of Candida species did not differ between elderly and younger patients (p >0.05). Resistance to fluconazole and voriconazole for non-Candida albicans species in elderly patients was approximately double that in younger patients. Host-related risk factors (e.g., underlying solid tumour, diabetes mellitus and chronic renal failure) and hospital-related factors (e.g., prior stay in an intensive care unit, mechanical ventilation, central vascular and urethral catheters placement) were identified more common in elderly patients. Elderly patients less often received triazoles and were less likely to receive antifungal therapies mostly because elderly or their guardians quit antifungal therapies. APACHE II scores and 30-day mortality were higher for elderly than younger patients (31.7% vs. 16.7%, p =0.032). For elderly patients, antifungal therapy administered before microbiological documentation was the only protective factor for death, whereas absence of antifungal therapies, receipt of mechanical ventilation and APACHE II score ≥20 were independent predictors of death.
Conclusions
Elderly patients with candidemia had poor prognoses characterized by certain host and hospital-related risk factors and special pathogen resistance features. More awareness of the burden of this disease is required, and the absence of antifungal therapies should be avoided to improve the prognoses of elderly patients with this severe infection.
doi:10.1186/s12879-014-0609-x
PMCID: PMC4247620  PMID: 25420435
Candidemia; Elderly; Antifungal agent; Risk factors; Death
25.  High Genetic Diversity and Novelty in Eukaryotic Plankton Assemblages Inhabiting Saline Lakes in the Qaidam Basin 
PLoS ONE  2014;9(11):e112812.
Saline lakes are intriguing ecosystems harboring extremely productive microbial communities in spite of their extreme environmental conditions. We performed a comprehensive analysis of the genetic diversity (18S rRNA gene) of the planktonic microbial eukaryotes (nano- and picoeukaryotes) in six different inland saline lakes located in the Qaidam Basin. The novelty level are high, with about 11.23% of the whole dataset showing <90% identity to any previously reported sequence in GenBank. At least 4 operational taxonomic units (OTUs) in mesosaline lakes, while up to eighteen OTUs in hypersaline lakes show very low CCM and CEM scores, indicating that these sequences are highly distantly related to any existing sequence. Most of the 18S rRNA gene sequence reads obtained in investigated mesosaline lakes is closely related to Holozoa group (48.13%), whereas Stramenopiles (26.65%) and Alveolates (10.84%) are the next most common groups. Hypersaline lakes in the Qaidam Basin are also dominated by Holozoa group, accounting for 26.65% of the total number of sequence reads. Notably, Chlorophyta group are only found in high abundance in Lake Gasikule (28.00%), whereas less represented in other hypersaline lakes such as Gahai (0.50%) and Xiaochaidan (1.15%). Further analysis show that the compositions of planktonic eukaryotic assemblages are also most variable between different sampling sites in the same lake. Out of the parameters, four show significant correlation to this CCA: altitude, calcium, sodium and potassium concentrations. Overall, this study shows important gaps in the current knowledge about planktonic microbial eukaryotes inhabiting Qaidam Basin (hyper) saline water bodies. The identified diversity and novelty patterns among eukaryotic plankton assemblages in saline lake are of great importance for understanding and interpreting their ecology and evolution.
doi:10.1371/journal.pone.0112812
PMCID: PMC4234628  PMID: 25401703

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