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1.  Radiofrequency ablation of hepatocellular carcinoma in difficult locations: Strategies and long-term outcomes 
AIM: To investigate the treatment strategies and long-term outcomes of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) in difficult locations and to compare the results with non-difficult HCC.
METHODS: From 2004 to 2012, a total of 470 HCC patients underwent ultrasound-guided percutaneous RFA. Among these HCC patients, 382 with tumors located ≤ 5 mm from a major vessel/bile duct (n = 87), from peripheral important structures (n = 232) or from the liver capsule (n = 63) were regarded as difficult cases. There were 331 male patients and 51 female patients, with an average age of 55.3 ± 10.1 years old. A total of 235 and 147 patients had Child-Pugh class A and class B liver function, respectively. The average tumor size was 3.4 ± 1.2 cm. Individual treatment strategies were developed to treat these difficult cases. During the same period, 88 HCC patients with tumors that were not in difficult locations served as the control group. In the control group, 74 patients were male, and 14 patients were female, with an average age of 57.4 ± 11.8 years old. Of these, 62 patients and 26 patients had Child-Pugh class A and class B liver function, respectively. Regular follow-up after RFA was performed to assess treatment efficacy. Survival results were generated from Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression model.
RESULTS: Early tumor necrosis rate in the difficult group was similar to that in the control group (97.6% vs 94.3%, P = 0.080). The complication rate in the difficult group was significantly higher than that in the control group (4.9% vs 0.8%, P = 0.041). The follow-up period ranged from 6 to 116 mo, with an average of 28 ± 22.4 mo. Local progression rate in the difficult group was significantly higher than that in the control group (12.7% vs 7.1%, P = 0.046). However, the 1-, 3-, 5-, and 7-year overall survival rates in the difficult group were not significantly different from those in the control group (84.3%, 54.4%, 41.2%, and 29.9% vs 92.5%, 60.3%, 43.2%, and 32.8%, respectively, P = 0.371). Additionally, a multivariate analysis revealed that tumor location was not a significant risk factor for survival.
CONCLUSION: There was no significant difference in long-term overall survival between the two groups even though the local progression rate was higher in the difficult group.
PMCID: PMC4316097  PMID: 25663774
Radiofrequency ablation; Ultrasound guidance; Hepatocellular carcinoma; Difficult location; Long-term outcome
2.  Identification of Associated SSR Markers for Yield Component and Fiber Quality Traits Based on Frame Map and Upland Cotton Collections 
PLoS ONE  2015;10(1):e0118073.
Detecting QTLs (quantitative trait loci) that enhance cotton yield and fiber quality traits and accelerate breeding has been the focus of many cotton breeders. In the present study, 359 SSR (simple sequence repeat) markers were used for the association mapping of 241 Upland cotton collections. A total of 333 markers, representing 733 polymorphic loci, were detected. The average linkage disequilibrium (LD) decay distances were 8.58 cM (r2 > 0.1) and 5.76 cM (r2 > 0.2). 241 collections were arranged into two subgroups using STRUCTURE software. Mixed linear modeling (MLM) methods (with population structure (Q) and relative kinship matrix (K)) were applied to analyze four phenotypic datasets obtained from four environments (two different locations and two years). Forty-six markers associated with the number of bolls per plant (NB), boll weight (BW), lint percentage (LP), fiber length (FL), fiber strength (FS) and fiber micornaire value (FM) were repeatedly detected in at least two environments. Of 46 associated markers, 32 were identified as new association markers, and 14 had been previously reported in the literature. Nine association markers were near QTLs (at a distance of less than 1–2 LD decay on the reference map) that had been previously described. These results provide new useful markers for marker-assisted selection in breeding programs and new insights for understanding the genetic basis of Upland cotton yields and fiber quality traits at the whole-genome level.
PMCID: PMC4311988  PMID: 25635680
3.  Low-Temperature Trapping of Photointermediates of the Rhodopsin E181Q Mutant 
SOJ biochemistry  2014;1(1):12.
Three active-site components in rhodopsin play a key role in the stability and function of the protein: 1) the counter-ion residues which stabilize the protonated Schiff base, 2) water molecules, and 3) the hydrogen-bonding network. The ionizable residue Glu-181, which is involved in an extended hydrogen-bonding network with Ser-186, Tyr-268, Tyr-192, and key water molecules within the active site of rhodopsin, has been shown to be involved in a complex counter-ion switch mechanism with Glu-113 during the photobleaching sequence of the protein. Herein, we examine the photobleaching sequence of the E181Q rhodopsin mutant by using cryogenic UV-visible spectroscopy to further elucidate the role of Glu-181 during photoactivation of the protein. We find that lower temperatures are required to trap the early photostationary states of the E181Q mutant compared to native rhodopsin. Additionally, a Blue Shifted Intermediate (BSI, λmax = 498 nm, 100 K) is observed after the formation of E181Q Bathorhodopsin (Batho, λmax = 556 nm, 10 K) but prior to formation of E181Q Lumirhodopsin (Lumi, λmax = 506 nm, 220 K). A potential energy diagram of the observed photointermediates suggests the E181Q Batho intermediate has an enthalpy value 7.99 KJ/mol higher than E181Q BSI, whereas in rhodopsin, the BSI is 10.02 KJ/mol higher in enthalpy than Batho. Thus, the Batho to BSI transition is enthalpically driven in E181Q and entropically driven in native rhodopsin. We conclude that the substitution of Glu-181 with Gln-181 results in a significant perturbation of the hydrogen-bonding network within the active site of rhodopsin. In addition, the removal of a key electrostatic interaction between the chromophore and the protein destabilizes the protein in both the dark state and Batho intermediate conformations while having a stabilizing effect on the BSI conformation. The observed destabilization upon this substitution further supports that Glu-181 is negatively charged in the early intermediates of the photobleaching sequence of rhodopsin.
PMCID: PMC4301618  PMID: 25621306
Rhodopsin; Photobleaching sequence; Photointermediates; Glu-181; E181Q; Blue-Shifted Intermediate (BSI); Absorption spectroscopy; Low-Temperature trapping
4.  B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets 
The Journal of Clinical Investigation  2014;124(10):4657-4667.
Classical IL-22–producing T helper cells (Th22 cells) mediate inflammatory responses independently of IFN-γ and IL-17; however, nonclassical Th22 cells have been recently identified and coexpress IFN-γ and/or IL-17 along with IL-22. Little is known about how classical and nonclassical Th22 subsets in human diseases are regulated. Here, we used samples of human blood, normal and peritumoral liver, and hepatocellular carcinoma (HCC) to delineate the phenotype, distribution, generation, and functional relevance of various Th22 subsets. Three nonclassical Th22 subsets constituted the majority of all Th22 cells in human liver and HCC tissues, although the classical Th22 subset was predominant in blood. Monocytes activated by TLR2 and TLR4 agonists served as the antigen-presenting cells (APCs) that most efficiently triggered the expansion of nonclassical Th22 subsets from memory T cells and classical Th22 subsets from naive T cells. Moreover, B7-H1–expressing monocytes skewed Th22 polarization away from IFN-γ and toward IL-17 through interaction with programmed death 1 (PD-1), an effect that can create favorable conditions for in vivo aggressive cancer growth and angiogenesis. Our results provide insight into the selective modulation of Th22 subsets and suggest that strategies to influence functional activities of inflammatory cells may benefit anticancer therapy.
PMCID: PMC4191045  PMID: 25244097
5.  A robust and versatile signal-on fluorescence sensing strategy based on SYBR Green I dye and graphene oxide 
A robust and versatile signal-on fluorescence sensing strategy was developed to provide label-free detection of various target analytes. The strategy used SYBR Green I dye and graphene oxide as signal reporter and signal-to-background ratio enhancer, respectively. Multidrug resistance protein 1 (MDR1) gene and mercury ion (Hg2+) were selected as target analytes to investigate the generality of the method. The linear relationship and specificity of the detections showed that the sensitive and selective analyses of target analytes could be achieved by the proposed strategy with low detection limits of 0.5 and 2.2 nM for MDR1 gene and Hg2+, respectively. Moreover, the strategy was used to detect real samples. Analytical results of MDR1 gene in the serum indicated that the developed method is a promising alternative approach for real applications in complex systems. Furthermore, the recovery of the proposed method for Hg2+ detection was acceptable. Thus, the developed label-free signal-on fluorescence sensing strategy exhibited excellent universality, sensitivity, and handling convenience.
PMCID: PMC4278783  PMID: 25565810
fluorescence; turn-on; SYBR Green I; graphene oxide; multidrug resistance protein 1 gene; Hg2+
6.  Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors 
ACS Medicinal Chemistry Letters  2013;4(12):1193-1197.
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM Kis < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
PMCID: PMC4027555  PMID: 24900629
Proviral insetion site in Moloney murine leukemia virus kinases inhibitors; Pim1 kinase inhibitor; Pim2 kinase inhibitor; Pim3 kinase inhibitor; pan-Pim kinase inhibitors
7.  A New Oligonucleotide Microarray for Detection of Pathogenic and Non-Pathogenic Legionella spp. 
PLoS ONE  2014;9(12):e113863.
Legionella pneumophila has been recognized as the major cause of legionellosis since the discovery of the deadly disease. Legionella spp. other than L. pneumophila were later found to be responsible to many non-pneumophila infections. The non-L. pneumophila infections are likely under-detected because of a lack of effective diagnosis. In this report, we have sequenced the 16S-23S rRNA gene internal transcribed spacer (ITS) of 10 Legionella species and subspecies, including L. anisa, L. bozemanii, L. dumoffii, L. fairfieldensis, L. gormanii, L. jordanis, L. maceachernii, L. micdadei, L. pneumophila subspp. fraseri and L. pneumophila subspp. pasculleii, and developed a rapid oligonucleotide microarray detection technique accordingly to identify 12 most common Legionella spp., which consist of 11 pathogenic species of L. anisa, L. bozemanii, L. dumoffii, L. gormanii, L. jordanis, L. longbeachae, L. maceachernii, L. micdadei, and L. pneumophila (including subspp. pneumophila, subspp. fraseri, and subspp. pasculleii) and one non-pathogenic species, L. fairfieldensis. Twenty-nine probes that reproducibly detected multiple Legionella species with high specificity were included in the array. A total of 52 strains, including 30 target pathogens and 22 non-target bacteria, were used to verify the oligonucleotide microarray assay. The sensitivity of the detection was at 1.0 ng with genomic DNA or 13 CFU/100 mL with Legionella cultures. The microarray detected seven samples of air conditioner-condensed water with 100% accuracy, validating the technique as a promising method for applications in basic microbiology, clinical diagnosis, food safety, and epidemiological surveillance. The phylogenetic study based on the ITS has also revealed that the non-pathogenic L. fairfieldensis is the closest to L. pneumophila than the nine other pathogenic Legionella spp.
PMCID: PMC4254607  PMID: 25469776
8.  Automatic Magnetic Resonance Spinal Cord Segmentation with Topology Constraints for Variable Fields of View 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.07.060.
Spinal cord segmentation is an important step in the analysis of neurological diseases such as multiple sclerosis. Several studies have shown correlations between disease progression and metrics relating to spinal cord atrophy and shape changes. Current practices primarily involve segmenting the spinal cord manually or semi-automatically, which can be inconsistent and time-consuming for large datasets. An automatic method that segments the spinal cord and cerebrospinal fluid from magnetic resonance images is presented. The method uses a deformable atlas and topology constraints to produce results that are robust to noise and artifacts. The method is designed to be easily extended to new data with different modalities, resolutions, and fields of view. Validation was performed on two distinct datasets. The first consists of magnetization transfer-prepared T2*-weighted gradient-echo MRI centered only on the cervical vertebrae (C1-C5). The second consists of T1-weighted MRI that cover both the cervical and portions of the thoracic vertebrae (C1-T4). Results were found to be highly accurate in comparison to manual segmentations. A pilot study was carried out to demonstrate the potential utility of this new method for research and clinical studies of multiple sclerosis.
PMCID: PMC3823375  PMID: 23927903
Atlas construction; topology-preserving segmentation; digital homeomorphism; spinal cord segmentation; magnetic resonance imaging
9.  Post-infectious myositis ossificans in medial, lateral pterygoid muscles: A case report and review of the literature 
Oncology Letters  2014;9(2):920-926.
Myositis ossificans (MO) is a disease where heterotropic bone forms within a muscle or other type of soft tissue. MO is classified into two groups, MO progressiva and post-traumatic MO. It rarely occurs in the masticatory muscles and thus, only 20 cases involving the masticatory muscles have been reported since 2001. The majority of the reported cases occurred due to trauma, repeated injury or surgical manipulation. However, in a small number of cases, no specific traumatic event was identified as the cause of MO. To the best of our knowledge, this is the first case of post-infectious MO to be reported in the medial and lateral pterygoid muscles.
PMCID: PMC4301508  PMID: 25621069
myositis ossificans; infection; pterygoid muscle; computed tomography
10.  Loss of Gsα Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors 
In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gsα activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gsα in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage.
PMCID: PMC4220542  PMID: 24806274
11.  Essential Role for Autophagy in the Maintenance of Immunological Memory Against Influenza Infection 
Nature medicine  2014;20(5):503-510.
Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy plays a critical role in the maintenance of memory B cells against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell-specific deletion of Atg7 (B/Atg7−/−) showed normal primary antibody responses after immunization against influenza, but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells and the maintenance of protective antibody responses required to combat infections.
PMCID: PMC4066663  PMID: 24747745
12.  CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small cell lung cancer 
CDKN2A(p16) inactivation is common in lung cancer and occurs via homozygous deletions (HD), methylation of promoter region, or point mutations. While p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown.
We determined all three p16 inactivation mechanisms using multiple methodologies for genomic status, methylation, RNA and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary NSCLC. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation.
p16 inactivation was the major mechanism of RB pathway perturbation in NSCLC, with HD being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking.
Our results confirm that all of the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.
PMCID: PMC3951422  PMID: 24077454
p16; CDKN2A; inactivation; homozygous deletion; methylation; lung cancer; adenocarcinoma; meta-analysis
13.  Barcoding Melting Curve Analysis for Rapid, Sensitive, and Discriminating Authentication of Saffron (Crocus sativus L.) from Its Adulterants 
BioMed Research International  2014;2014:809037.
Saffron (Crocus sativus L.) is one of the most important and expensive medicinal spice products in the world. Because of its high market value and premium price, saffron is often adulterated through the incorporation of other materials, such as Carthamus tinctorius L. and Calendula officinalis L. flowers, Hemerocallis L. petals, Daucus carota L. fleshy root, Curcuma longa L. rhizomes, Zea may L., and Nelumbo nucifera Gaertn. stigmas. To develop a straightforward, nonsequencing method for rapid, sensitive, and discriminating detection of these adulterants in traded saffron, we report here the application of a barcoding melting curve analysis method (Bar-MCA) that uses the universal chloroplast plant DNA barcoding region trnH-psbA to identify adulterants. When amplified at DNA concentrations and annealing temperatures optimized for the curve analysis, peaks were formed at specific locations for saffron (81.92°C) and the adulterants: D. carota (81.60°C), C. tinctorius (80.10°C), C. officinalis (79.92°C), Dendranthema morifolium (Ramat.) Tzvel. (79.62°C), N. nucifera (80.58°C), Hemerocallis fulva (L.) L. (84.78°C), and Z. mays (84.33°C). The constructed melting curves for saffron and its adulterants have significantly different peak locations or shapes. In conclusion, Bar-MCA could be a faster and more cost-effective method to authenticate saffron and detect its adulterants.
PMCID: PMC4274822  PMID: 25548775
14.  Energy Detection Based on Undecimated Discrete Wavelet Transform and Its Application in Magnetic Anomaly Detection 
PLoS ONE  2014;9(10):e110829.
Magnetic anomaly detection (MAD) is a passive approach for detection of a ferromagnetic target, and its performance is often limited by external noises. In consideration of one major noise source is the fractal noise (or called 1/f noise) with a power spectral density of 1/fa (0
PMCID: PMC4208775  PMID: 25343484
Hypospadias is one of the most common congenital malformations of the genitourinary tract in males. It is an incomplete fusion of urethral folds early in fetal development and may be associated with other malformations of the genital tract. The etiology is poorly understood and may be hormonal, genetic, or environmental, but most often is idiopathic or multifactorial. Among many possible risk factors identified, of particular importance is low birth weight, which is defined in various ways in the literature. No mechanism has been identified for the association of low birth weight and hypospadias, but some authors propose placental insufficiency as a common inciting factor. Currently, there is no standardized approach for evaluating children with hypospadias in the setting of intrauterine growth restriction. We reviewed the available published literature on the association of hypospadias and growth restriction to determine whether it should be considered a separate entity within the category of disorders of sexual differentiation.
PMCID: PMC4203859  PMID: 25337123
Intrauterine growth restriction; Fetal growth restriction; Small for gestational age; Low birth weight; Placental insufficiency; Hypospadias
World Journal of Gastroenterology : WJG  2014;20(38):14010-14017.
AIM: To investigate the relationship between Apolipoprotein C3 (APOC3) (-455T>C) polymorphism and nonalcoholic fatty liver disease (NAFLD) in the Southern Chinese Han population.
METHODS: In this prospective case-control study, we recruited 300 NAFLD patients and 300 healthy controls to a cohort representing Southern Chinese Han population at The First Affiliated Hospital, Sun Yat-sen University, from January to December 2012. Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing were used to genotype the APOC3 (-455T>C) variants.
RESULTS: After adjusting for age, gender, and body-mass index, TC and CC genotypes were found to increase the susceptibility to NAFLD compared to the TT genotype, with adjusted odds ratios (ORs) of 1.77 (95%CI: 1.16-2.72) and 2.80 (95%CI: 1.64-4.79), respectively. Further stratification analysis indicated that carriers of the CC genotype was more susceptible to insulin resistance (IR) than those of the TT genotype, with an OR of 3.24 (95%CI: 1.52-6.92). The CC genotype also was associated with a significantly higher risk of hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL) (P < 0.05). No association was found between the APOC3 (-455T>C) polymorphism and obesity, impaired glucose tolerance, hyperuricemia, hypercholesterolemia, or high levels of low-density lipoprotein cholesterol (LDL) (P > 0.05).
CONCLUSION: APOC3 (-455T>C) genetic variation is involved in the susceptibility to developing NAFLD, IR, hypertension, hypertriglyceridemia, and low HDL in the Southern Chinese Han population.
PMCID: PMC4194587  PMID: 25320541
Apolipoprotein C3; Nonalcoholic fatty liver disease; Insulin resistance; Metabolic disorder; Polymorphism
PLoS ONE  2014;9(10):e109634.
Recent studies have demonstrated the protective effect of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases. Increased levels of the potential ALDH2 substrate 4-hydroxynonenal (4-HNE) are involved in myocardial/cerebral ischemia accompanied by a high level of oxidative stress. In this investigation, we first performed a case-control study to explore the potential association of ALDH2 rs671 polymorphism and post-stroke epilepsy (PSE). Then, we performed an in vitro study to determine whether the overexpression of ALDH2 could decrease the level of oxidative stress and the apoptosis ratio induced by 4-HNE. There was a significant difference in the distribution of the allele and genotype frequencies of the rs671 polymorphism between PSE patients and ischemic stroke (IS) patients. Individuals with the rs671 A allele showed significantly higher levels of plasma 4-HNE. The overexpression of ALDH2 partially blocked the increased levels of malondialdehyde (MDA), reactive oxygen species (ROS) and apoptosis ratio induced by 4-HNE and also partially restored the ALDH2 activity in PC12 cells; these effects were reversed in the presence of εV1-2. Our results suggest that the ALDH2 rs671 polymorphism is associated with PSE susceptibility and affects the 4-HNE levels. Targeting ALDH2 might be a useful strategy for the treatment or prevention of PSE.
PMCID: PMC4196934  PMID: 25313998
Journal of the American Chemical Society  2013;135(40):10.1021/ja408206e.
The outer membrane protein G (OmpG) is a monomeric 33 kDa 14-stranded β-barrel membrane protein functioning as a non-specific porin for the uptake of oligosaccharides in E. coli. Two different crystal structures of OmpG obtained at different values of pH suggest a pH-gated pore opening mechanism. In these structures, extracellular loop 6 extends away from the barrel wall at neutral pH, but is folded back into the pore lumen at low pH, blocking transport through the pore. Loop 6 was invisible in a previously published solution NMR structure of OmpG in DPC micelles, presumably due to conformational exchange on an intermediate NMR time-scale. Here we present an NMR paramagnetic relaxation enhancement (PRE)-based approach to visualize the conformational dynamics of loop 6 and to calculate conformational ensembles that explain the pH-gated opening and closing of the OmpG channel. The different loop conformers detected by the PRE ensemble calculations were validated by disulfide cross-linking of strategically engineered cysteines and electrophysiological single channel recordings. The results indicate a more dynamically regulated channel opening and closing than previously thought and reveal additional membrane-associated conformational ensembles at pH 6.3 and 7.0. We anticipate this approach to be generally applicable to detect and characterize functionally important conformational ensembles of membrane proteins.
PMCID: PMC3863726  PMID: 24020969
BMC Ophthalmology  2014;14(1):119.
To determine the outcome of central retinal vein occlusion (CRVO) in pre-existing glaucoma and the predisposing factors of developing neovascular glaucoma (NVG).
We retrospectively assessed a pre-existing glaucoma CRVO group and a non-glaucoma CRVO group to elucidate the demographics, clinical course and ocular parameters of these two cohorts. Among the pre-existing glaucoma cases, the predisposing factors for the development of NVG were monitored, including the retinal capillary non-perfusion status, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) at presentation.
Of 642 CRVO patients reviewed in this 10-year cohort study, 60 (9.3%) had pre-existing glaucoma at a mean follow-up of 30.8 months, including 28 (4.4%) primary open angle glaucoma (POAG), 27 (4.2%) primary angle closure glaucoma (PACG), and 5 (0.8%) normal tension glaucoma (NTG) cases. Although the presence of glaucoma in the CRVO eyes was not significantly associated with the risk of developing NVG, the incidence of developing NVG in pre-existing glaucoma eyes was significantly higher in the group with IOP greater than 20 mmHg at CRVO presentation (P = 0.02, Chi-square test) as well as in the ischemic CRVO group compared to the non-ischemic patients (P = 0.005, Fisher’s exact test). Overall, 20% of pre-existing glaucoma patients needed glaucoma surgery after a CRVO event, including 11.7% of patients who developed iris neovascularisation (INV) and 8.3% of patients who developed a high IOP without INV.
Both the retinal non-perfusion status and uncontrolled IOP contribute to NVG in patients with pre-existing glaucoma after CRVO. Following CRVO, glaucoma surgery is necessary for pre-existing glaucoma cases with intractable elevated IOP with or without INV.
PMCID: PMC4193090  PMID: 25282154
Neovascular glaucoma; Central retinal vein occlusion with pre-existing glaucoma; Retinal non-perfusion status; Intraocular pressure; Predisposing factors
PLoS ONE  2014;9(10):e108180.
To investigate the underlying physiological mechanisms of the structural differences in gray matter (GM) and white matter (WM) associated with obesity in young Chinese adults.
Materials and Methods
A total of 49 right-handed obese or overweight (n = 22, mean age 31.72±8.04 years) and normal weight (n = 27, mean age 29.04±7.32 years) Han Chinese individuals were recruited. All participants underwent voxel-based morphometry analysis of T1-weighted MRI and tract-based spatial statistics analysis of diffusion tensor imaging. Partial correlation analysis was performed between the physiological data obtained and the abnormal structural alterations.
In the OO group, GM atrophy occurred in the left prefrontal cortex, bilateral cingulate gyrus, and the right temporal lobe, while enlargement was observed in the bilateral putamen. WM atrophy was observed predominantly in the regions that regulate food intake, such as the bilateral basal ganglia, the right amygdala, and the left insula. The OO group exhibited lower fractional anisotropy (FA) in bilateral frontal corticospinal tracts and the right brainstem. Significant negative correlations were observed between FA values of those three clusters and BMI, and waist circumference, while the volume of bilateral putamen positively correlated with both BMI and waist circumference. High plasma LDL levels were correlated with low FA values in the right frontal corticospinal tract. Interestingly, the negative correlation was limited to male participants.
Obesity-related alterations of GM and WM volumes were observed predominantly in food reward circuit, which may motivate abnormal dietary intake. Further, early elevated plasma LDL might contribute to low right frontal FA values of male adults, which requires further demonstration by larger-scale and longitudinal studies.
PMCID: PMC4184805  PMID: 25279729
PLoS ONE  2014;9(9):e106754.
Mineral Trioxide Aggregate (MTA) was widely used as a root-end filling material and for vital pulp therapy. A significant disadvantage to MTA is the prolonged setting time has limited the application in endodontic treatments. This study examined the physicochemical properties and biological performance of novel partially stabilized cements (PSCs) prepared to address some of the drawbacks of MTA, without causing any change in biological properties. PSC has a great potential as the vital pulp therapy material in dentistry.
This study examined three experimental groups consisting of samples that were fabricated using sol-gel processes in C3S/C3A molar ratios of 9/1, 7/3, and 5/5 (denoted as PSC-91, PSC-73, and PSC-55, respectively). The comparison group consisted of MTA samples. The setting times, pH variation, compressive strength, morphology, and phase composition of hydration products and ex vivo bioactivity were evaluated. Moreover, biocompatibility was assessed by using lactate dehydrogenase to determine the cytotoxicity and a cell proliferation (WST-1) assay kit to determine cell viability. Mineralization was evaluated using Alizarin Red S staining.
Crystalline phases, which were determined using X-ray diffraction analysis, confirmed that the C3A contents of the material powder differed. The initial setting times of PSC-73 and PSC-55 ranged between 15 and 25 min; these values are significantly (p<0.05, ANOVA and post-hoc test) lower than those obtained for MTA (165 min) and PSC-91 (80.5 min). All of the PSCs exhibited ex vivo bioactivity when immersed in simulated body fluid. The biocompatibility results for all of the tested cements were as favorable as those of the negative control, except for PSC-55, which exhibited mild cytotoxicity.
PSC-91 is a favorable material for vital pulp therapy because it exhibits optimal compressive strength, a short setting time, and high biocompatibility and bioactivity.
PMCID: PMC4172564  PMID: 25247808
Burkitt lymphoma (BL) is a highly aggressive subtype of non-Hodgkin lymphomas (NHL). Lymphoma related granulomatous reaction rarely occurs in sporadic BL. Herein, we describe the first case of HIV related Burkitt lymphoma with florid granulomatous reaction. A 41-year-old HIV-positive Chinese male presented lymphadenopathy in the right cervical region for 3 months. The enlarged lymph node biopsies revealed the presence of prominent granulomas of varying size with Langhans giant cells, leading to the misdiagnosis of tuberculous lymphadenitis in other hospital. Subsequently, the case was sent to us for consultation. The morphology, immunophenotype, special staining, interphase FISH analysis and blood tests confirmed a diagnosis of HIV related Burkitt lymphoma with granulomatous reaction. Without radiotherapy and chemotherapy, the patient was alive and well with no evidence of lymphoma during the observation period of 24 months. The case suggested that lymphoma with florid granulomatous reaction can easily be misdiagnosed as benign lesions since the large number of epithelioid granulomas could obscure the primary lesion. Moreover, the granulomatous reaction may be an indicator for favorable prognosis in HIV related Burkitt lymphoma.
PMCID: PMC4230138  PMID: 25400794
Human immunodeficiency virus related Burkitt lymphoma; granulomatous reaction; prognosis
Developmental cell  2014;29(2):217-232.
A substantial amount of mitochondrial energy is required for cell cycle progression. However, the mechanisms coordinating the mitochondrial respiration with G2/M transition, a critical step in cell division, remains to be elucidated. Here we show that a fraction of cell cycle CyclinB1/Cdk1 proteins localizes into the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins including the complex I (CI) subunits in the respiratory chain. The CyclinB1/Cdk1-mediated CI subunit phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function. Mitochondria-targeted CyclinB1/Cdk1 increases mitochondrial respiration with enhanced oxygen consumption and ATP generation, which provides cells with efficient bioenergy for G2/M transition and shortens overall cycling time. Thus, CyclinB1/Cdk1-mediated phosphorylation of mitochondrial substrates allows cells to sense and respond to an increased energy demand for G2/M transition, and subsequently to up-regulate mitochondrial respiration for a successful cell cycle progression.
PMCID: PMC4156313  PMID: 24746669
CyclinB1/Cdk1; Mitochondrial respiration; Phosphorylation; Cell cycle; G2/M-checkpoint
Rubella remains a social and economic burden due to the high incidence of congenital rubella syndrome (CRS) in some countries. For this reason, an accurate and efficient high-throughput measure of antibody response to vaccination is an important tool. In order to measure rubella-specific neutralizing antibodies in a large cohort of vaccinated individuals, a high-throughput immunocolorimetric system was developed. Statistical interpolation models were applied to the resulting titers to refine quantitative estimates of neutralizing antibody titers relative to the assayed neutralizing antibody dilutions. This assay, including the statistical methods developed, can be used to assess the neutralizing humoral immune response to rubella virus and may be adaptable for assessing the response to other viral vaccines and infectious agents.
PMCID: PMC3957678  PMID: 24391140
Oncotarget  2014;5(18):8637-8650.
Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IM-resistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34+ treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.
PMCID: PMC4226710  PMID: 25226617
CML; BCR-ABL; leukemic stem cells; JAK2; TKI resistance; BMS-911543

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