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1.  Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients 
World Journal of Gastroenterology : WJG  2015;21(36):10443-10452.
AIM: To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis.
METHODS: Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups.
RESULTS: A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically.
CONCLUSION: Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.
PMCID: PMC4579891  PMID: 26420971
Chemoembolization; Hepatic arterial infusion chemotherapy; Oxaliplatin; Hepatocellular carcinoma
2.  TGF-β1-509C/T polymorphism and the risk of ESCC in a Chinese Han population 
Background: The studies investigating whether transforming growth factor (TGF)-β1-509C/T polymorphism is associated with the risk of ESCC is inconsistent. Methods: The TGF-β1-509C/T genotypes were determined by using a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay and DNA sequencing analysis. The differences in demographic variables and genotype distributions of TGF-β1-509C/T polymorphism between ESCC patients and controls were calculated by Pearson’s Chi square test. Associations between TGF-β1-509C/T polymorphism genotypes and ESCC risk were estimated by OR and their 95% CIs computed using unconditional logistic regression model. Results: There was a significant difference of TGF-β1-509C/T polymorphism genotype distribution between ESCC group and control group (P<0.001). With the CC genotype as reference, the adjusted OR for CT genotype reached to 0.78 (95% CI: 0.65-0.89; P=0.041), and the adjusted OR for TT homozygous carriers was 0.52 (95% CI: 0.33-0.78; P=0.017). The T allele carriage also presented a lower risk for ESCC (adjusted OR=0.43; 95% CI, 0.29-0.71; P=0.009). Conclusion: TGF-β1-509C/T polymorphism may contributes to ESCC susceptibility in Chinese population.
PMCID: PMC4565357  PMID: 26379974
TGF-β1; polymorphism; ESCC; risk
3.  A rare case of pulmonary sclerosing hemagioma with lymph node metastasis and review of the literature 
Pulmonary sclerosing hemagioma (SH) is an uncommon tumor with malignance potential. Clinically this disease is regarded as benign but extremely rare cases can have lymph node metastasis. Up to date, there have been only very few reports concerning SH with lymph node metastasis. In this paper we reported one pulmonary SH case with lymph node metastasis and additionally overviewed the clinical and pathological features of SH. A young-aged female was found incidentally to have a nodule in the right upper lung. This patient presented no cough, no hemoptysis and chest pain. Computed tomography (CT) scan indicated a large mass in the right upper lung and enlarged lymph nodes in the right hilum. The patient underwent lobectomy of the right upper lung. Histologically, the tumor demonstrated typical features of SH and was consisted of angiomatoid areas, sclerosis, papillary structures lined with cuboidal cells and sheets of round to polygonal cells. Polygonal cells in some solid areas presented abnormal enlarged nuclei and increased karyoplasmic ratio; tumor giant cells were noted; whereas mitosis was not observed. One peribronchial lymph node was noted for SH metastasis and the metastatic tissue were consisted of polygonal cells. Immunohistochemistry (IHC) revealed that both surface-lining cuboidal and polygonal cells expressed EMA and thyroid transcription factor 1 (TTF-1), but were negative for CD34, VIII factor, CD68 and Claratinin. The polygonal cells showed relatively higher expression of Ki-67 and p53 than the surface-lining cells. Postoperatively, the patient received no chemotherapy or radiotherapy and no recurrence 2 years after surgery was noted.
PMCID: PMC4555772  PMID: 26339444
Sclerosing hemangioma (SH); pulmonary SH; lymph node metastasis
4.  Ultrathin Carbon with Interspersed Graphene/Fullerene-like Nanostructures: A Durable Protective Overcoat for High Density Magnetic Storage 
Scientific Reports  2015;5:11607.
One of the key issues for future hard disk drive technology is to design and develop ultrathin (<2 nm) overcoats with excellent wear- and corrosion protection and high thermal stability. Forming carbon overcoats (COCs) having interspersed nanostructures by the filtered cathodic vacuum arc (FCVA) process can be an effective approach to achieve the desired target. In this work, by employing a novel bi-level surface modification approach using FCVA, the formation of a high sp3 bonded ultrathin (~1.7 nm) amorphous carbon overcoat with interspersed graphene/fullerene-like nanostructures, grown on magnetic hard disk media, is reported. The in-depth spectroscopic and microscopic analyses by high resolution transmission electron microscopy, scanning tunneling microscopy, time-of-flight secondary ion mass spectrometry, and Raman spectroscopy support the observed findings. Despite a reduction of ~37 % in COC thickness, the FCVA-processed thinner COC (~1.7 nm) shows promising functional performance in terms of lower coefficient of friction (~0.25), higher wear resistance, lower surface energy, excellent hydrophobicity and similar/better oxidation corrosion resistance than current commercial COCs of thickness ~2.7 nm. The surface and tribological properties of FCVA-deposited COC was further improved after deposition of lubricant layer.
PMCID: PMC4479824  PMID: 26109208
5.  Rice ragged stunt virus-induced apoptosis affects virus transmission from its insect vector, the brown planthopper to the rice plant 
Scientific Reports  2015;5:11413.
Most plant viruses that seriously damage agricultural crops are transmitted by insects. However, the mechanisms enabling virus transmission by insect vectors are poorly understood. The brown planthopper (Nilaparvata lugens) is one of the most serious rice pests, causing extensive damage to rice plants by sucking the phloem sap and transmitting viruses, including Rice ragged stunt virus (RRSV). In this study, we investigated the mechanisms of RRSV transmission from its insect vector to the rice plant in vivo using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and RNA interference technology. RRSV induced apoptosis in the salivary gland cells of its insect vector, N. lugens. The RRSV-induced apoptosis was regulated through a caspase-dependent manner, and inhibition of the expression of N. lugens caspase-1 genes significantly interfered with virus transmission. Our findings establish a link between virus-associated apoptosis and virus transmission from the insect vector to the host plant.
PMCID: PMC4466780  PMID: 26073458
6.  Linoleic acid induces red blood cells and hemoglobin damage via oxidative mechanism 
Hidden blood loss typically occurs following total hip arthroplasty (THA) and total knee arthroplasty (TKA) and is thought to be related to free fatty acid (FFA). To study the effect of linoleic acid on red blood cells and to examine the pathogenesis of hidden blood loss in vivo, we generated an animal model by injecting linoleic acid into the tail veins of rats. We collected blood samples and determined red blood cell count (RBC) and levels of hemoglobin (Hb), as well as the oxidation and reducing agents in the blood, including glutathione peroxidase (GSH-PX), total superoxide dismutase (T-SOD), hydrogen peroxide (H2O2), and ferryl hemoglobin (Fe4+ = O2-), which is generated by the oxidation of Hb. Hidden blood loss occurred when linoleic acid was administered at a concentration of 60 mmol/L; RBC and Hb levels were significantly reduced by 24 h post-injection. This was followed by erythrocyte deformation, reduced activity of GSH-PX and T-SOD, and decreased levels of H2O2. This was accompanied by an increase in ferryl species, which likely contributes to oxidative stress in vivo. Our findings suggest that linoleic acid enhances acute red blood cell injury. Hb and RBC began to increase by 72 h, potentially resulting from linoleic acid metabolism. Thus, elevated levels of linoleic acid in the blood cause acute oxidative damage to red blood cells, eventually leading to partial acute anemia. These findings highlight the pathophysiology underlying hidden blood loss.
PMCID: PMC4503070  PMID: 26191198
Linoleic acid; free fatty acid; erythrocyte damage; oxidative stress; hidden blood loss
7.  A novel association of adenosine deaminase with paroxysmal atrial fibrillation: a propensity score analysis from a case-control study 
Journal of Thoracic Disease  2015;7(4):662-671.
Prior work has identified age, body mass index, underlying heart disease, and other comorbidities as risk factors for atrial fibrillation. To date, studies have examined single baseline measures of traditional risk factors, and data on biomarker associations are lacking.
We sought to explore novel biochemical measures possibly associated with incident PAF after balancing the traditional risk factors.
Men or women aged ≥18 years that were hospitalized between 1st Jan. 2010 and 31st Dec. 2013 for paroxysmal atrial fibrillation (PAF) and for health checkup (non-PAF) were included. We used propensity score methods to mitigate the influence of the nonrandom selection of PAF and non-PAF patients. Logistic regression was applied for analysis of risk factors for PAF.
A total of 1,802 eligible patients were identified, in whom, 895 patients had at least one exclusion criterion. After excluding these patients, the total analytic cohort numbered 907 patients. Of these, 779 patients were for control group and 128 patients were for PAF group. Propensity score matching was used to obtain a balanced cohort of 124 patients per group. The PAF and non-PAF groups were well matched on demographic and clinical characteristics after propensity matching. Risk factors for PAF on multivariate stepwise logistic regression model included adenosine deaminase (ADA) [odds ratio (OR) =0.9160, P=0.015, 95% confidence interval (CI): 0.8536-0.9829], mitral valvular regurgitation (OR =3.4611, P=0.001, 95% CI: 1.7000-7.0467) and left atrial diameter (OR =1.0913, P=0.001, 95% CI: 1.0387-1.1465). Only the ADA was a protective factor for the occurrence of PAF.
The ADA seems to be associated with PAF. The current study provides new insights into the prevention and treatment of PAF.
PMCID: PMC4419295  PMID: 25973232
Risk factors; adenosine deaminase (ADA); paroxysmal atrial fibrillation (PAF); propensity score
8.  Goal attainments and their discrepancies for low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) in over 2,000 Chinese patients with known coronary artery disease or type 2 diabetes 
Low density lipoprotein cholesterol (LDL-C) is primary treatment target for patients with dislipidemia. The apolipoprotein B (apo B), an emerging biomarker for cardiovascular risk prediction, appears to be superior to the LDL-C. However, little is known about goal attainments and their discrepancies for LDL-C and apo B in Chinese patients with known CAD or DM.
A total of 2,172 hospitalized patients with known coronary artery disease (CAD) or DM, aged >27 years of old, were enrolled. The success rates for apo B and LDL-C goal attainments were evaluated and compared by categorization and by sex.
When the success rates for apo B were compared with the ones for LDL-C, the former was higher than the latter across all categorizations, with the statistically significant differences seen in all patients, CAD alone and DM alone (P<0.0001), but not in coexistence of CAD and DM (P=0.190). The trend toward to higher success rates for LDL-C and apo B goal attainments in men than in women were noteworthy across all categorizations although only in all patients and in DM alone patients were the statistically significant differences found (P<0.01).
The LDL-C lags behind the apo B in goal attainments in Chinese patients. Whether these discrepancies are associated with the occurrence differences for CAD and for stroke between the East Asia and the Western countries warrants further study.
PMCID: PMC4420678  PMID: 25984449
Apolipoprotein B (apo B); low density lipoprotein cholesterol (LDL-C); goal attainments; coronary artery disease (CAD); diabetes mellitus (DM)
9.  Switchable sensitizers stepwise lighting up lanthanide emissions 
Scientific Reports  2015;5:9335.
Analagous to a long-ranged rocket equipped with multi-stage engines, a luminescent compound with consistent emission signals across a large range of concentrations from two stages of sensitizers can be designed. In this approach, ACQ, aggregation-caused quenching effect of sensitizers, would stimulate lanthanide emission below 10−4 M, and then at concentrations higher than 10−3 M, the “aggregation-induced emission” (AIE) effect of luminophores would be activated with the next set of sensitizers for lanthanide emission. Simultaneously, the concentration of the molecules could be monitored digitally by the maximal excitation wavelengths, due to the good linear relationship between the maximal excitation wavelengths and the concentrations {lg(M)}. This model, wherein molecules are assembled with two stages (both AIE and ACQ effect) of sensitizers, may provide a practicable strategy for design and construction of smart lanthanide bioprobes, which are suitable in complicated bioassay systems in which concentration is variable.
PMCID: PMC4366845  PMID: 25791467
10.  Differential Gene Expression in Ovaries of Qira Black Sheep and Hetian Sheep Using RNA-Seq Technique 
PLoS ONE  2015;10(3):e0120170.
The Qira black sheep and the Hetian sheep are two local breeds in the Northwest of China, which are characterized by high-fecundity and low-fecundity breed respectively. The elucidation of mRNA expression profiles in the ovaries among different sheep breeds representing fecundity extremes will helpful for identification and utilization of major prolificacy genes in sheep. In the present study, we performed RNA-seq technology to compare the difference in ovarian mRNA expression profiles between Qira black sheep and Hetian sheep. From the Qira black sheep and the Hetian sheep libraries, we obtained a total of 11,747,582 and 11,879,968 sequencing reads, respectively. After aligning to the reference sequences, the two libraries included 16,763 and 16,814 genes respectively. A total of 1,252 genes were significantly differentially expressed at Hetian sheep compared with Qira black sheep. Eight differentially expressed genes were randomly selected for validation by real-time RT-PCR. This study provides a basic data for future research of the sheep reproduction.
PMCID: PMC4366253  PMID: 25790350
12.  Anterior cervical discectomy and fusion versus anterior cervical corpectomy and fusion in the treatment of multilevel cervical spondylotic myelopathy: systematic review and a meta-analysis 
To date, the decision to treat multilevel cervical spondylotic myelopathy (CSM) with anterior cervical discectomy and fusion (ACDF) or anterior cervical corpectomy and fusion (ACCF) remains controversial. Therefore, we conducted a meta-analysis to quantitatively determine the efficacy of ACDF and ACCF in the treatment of multilevel CSM.
We searched several databases for related research articles published in English or Chinese. We extracted and assessed the data independently. We determined the pooled data, data heterogeneity, and overall effect, respectively.
We identified 15 eligible studies with 1,368 patients. We found that blood loss and numbers of complications during surgery in ACDF were significantly less that in ACCF; however, other clinical outcomes, such as operation time, bone fusion failure, post Japanese Orthopedic Association scores, recovery rates, and visual analog scale scores between ACDF and ACCF with multilevel CSM were not significantly different.
Our results strongly suggest that surgical treatments of multilevel CSM are similar in terms of most clinical outcomes using ACDF or ACCF.
PMCID: PMC4321642  PMID: 25673996
meta-analysis; therapy; anterior cervical discectomy and fusion; anterior cervical corpectomy and fusion; cervical spondylotic myelopathy
13.  Genomes of the rice pest brown planthopper and its endosymbionts reveal complex complementary contributions for host adaptation 
Genome Biology  2014;15(12):521.
The brown planthopper, Nilaparvata lugens, the most destructive pest of rice, is a typical monophagous herbivore that feeds exclusively on rice sap, which migrates over long distances. Outbreaks of it have re-occurred approximately every three years in Asia. It has also been used as a model system for ecological studies and for developing effective pest management. To better understand how a monophagous sap-sucking arthropod herbivore has adapted to its exclusive host selection and to provide insights to improve pest control, we analyzed the genomes of the brown planthopper and its two endosymbionts.
We describe the 1.14 gigabase planthopper draft genome and the genomes of two microbial endosymbionts that permit the planthopper to forage exclusively on rice fields. Only 40.8% of the 27,571 identified Nilaparvata protein coding genes have detectable shared homology with the proteomes of the other 14 arthropods included in this study, reflecting large-scale gene losses including in evolutionarily conserved gene families and biochemical pathways. These unique genomic features are functionally associated with the animal’s exclusive plant host selection. Genes missing from the insect in conserved biochemical pathways that are essential for its survival on the nutritionally imbalanced sap diet are present in the genomes of its microbial endosymbionts, which have evolved to complement the mutualistic nutritional needs of the host.
Our study reveals a series of complex adaptations of the brown planthopper involving a variety of biological processes, that result in its highly destructive impact on the exclusive host rice. All these findings highlight potential directions for effective pest control of the planthopper.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0521-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4269174  PMID: 25609551
14.  Controlling Cyanobacterial Blooms in Hypertrophic Lake Taihu, China: Will Nitrogen Reductions Cause Replacement of Non-N2 Fixing by N2 Fixing Taxa? 
PLoS ONE  2014;9(11):e113123.
Excessive anthropogenic nitrogen (N) and phosphorus (P) inputs have caused an alarming increase in harmful cyanobacterial blooms, threatening sustainability of lakes and reservoirs worldwide. Hypertrophic Lake Taihu, China’s third largest freshwater lake, typifies this predicament, with toxic blooms of the non-N2 fixing cyanobacteria Microcystis spp. dominating from spring through fall. Previous studies indicate N and P reductions are needed to reduce bloom magnitude and duration. However, N reductions may encourage replacement of non-N2 fixing with N2 fixing cyanobacteria. This potentially counterproductive scenario was evaluated using replicate, large (1000 L), in-lake mesocosms during summer bloom periods. N+P additions led to maximum phytoplankton production. Phosphorus enrichment, which promoted N limitation, resulted in increases in N2 fixing taxa (Anabaena spp.), but it did not lead to significant replacement of non-N2 fixing with N2 fixing cyanobacteria, and N2 fixation rates remained ecologically insignificant. Furthermore, P enrichment failed to increase phytoplankton production relative to controls, indicating that N was the most limiting nutrient throughout this period. We propose that Microcystis spp. and other non-N2 fixing genera can maintain dominance in this shallow, highly turbid, nutrient-enriched lake by outcompeting N2 fixing taxa for existing sources of N and P stored and cycled in the lake. To bring Taihu and other hypertrophic systems below the bloom threshold, both N and P reductions will be needed until the legacy of high N and P loading and sediment nutrient storage in these systems is depleted. At that point, a more exclusive focus on P reductions may be feasible.
PMCID: PMC4236137  PMID: 25405474
15.  Brown Planthopper Nudivirus DNA Integrated in Its Host Genome 
Journal of Virology  2014;88(10):5310-5318.
The brown planthopper (BPH), Nilaparvata lugens (Hemiptera:Delphacidae), is one of the most destructive insect pests of rice crops in Asia. Nudivirus-like sequences were identified during the whole-genome sequencing of BPH. PCR examination showed that the virus sequences were present in all of the 22 BPH populations collected from East, Southeast, and South Asia. Thirty-two of the 33 nudivirus core genes were identified, including 20 homologues of baculovirus core genes. In addition, several gene clusters that were arranged collinearly with those of other nudiviruses were found in the partial virus genome. In a phylogenetic tree constructed using the supermatrix method, the original virus was grouped with other nudiviruses and was closely related to polydnavirus. Taken together, these data indicated that the virus sequences belong to a new member of the family Nudiviridae. More specifically, the virus sequences were integrated into the chromosome of its insect host during coevolution. This study is the first report of a large double-stranded circular DNA virus genome in a sap-sucking hemipteran insect.
IMPORTANCE This is the first report of a large double-stranded DNA virus integrated genome in the planthopper, a plant sap-sucking hemipteran insect. It is an exciting addition to the evolutionary story of bracoviruses (polydnaviruses), nudiviruses, and baculoviruses. The results on the virus sequences integrated in the chromosomes of its insect host also represent a story of successful coevolution of an invertebrate virus and a plant sap-sucking insect.
PMCID: PMC4019104  PMID: 24574410
16.  Vitreoscilla hemoglobin promotes Salecan production by Agrobacterium sp. ZX09*  
Salecan is a novel exopolysaccharide produced by the strain Agrobacterium sp. ZX09, and it is composed of only glucose monomers. The unique chemical composition and excellent physicochemical properties make Salecan a promising material for applications in coagulation, lubrication, protection against acute liver injury, and alleviating constipation. In this study, we cloned the Vitreoscilla hemoglobin gene into a broad-host-range plasmid pCM158. Without antibiotic selection, there was negligible loss of the plasmid in the host Agrobacterium sp. ZX09 after one passage of cultivation. The expression of Vitreoscilla hemoglobin was demonstrated by carbon monoxide (CO) difference spectrum. The engineered strain Agrobacterium sp. ZX09 increased Salecan yield by 30%. The other physiological changes included its elevated respiration rate and cellular invertase activity.
PMCID: PMC4228510  PMID: 25367790
Salecan; Vitreoscilla hemoglobin; Agrobacterium sp. ZX09; Invertase; Respiration rate
17.  Association between cardiothoracic ratio, left ventricular size and systolic function in patients undergoing computed tomography coronary angiography 
The present study aimed to investigate the association between cardiothoracic ratio (CTR) and left ventricular (LV) systolic function parameters in patients with or without preserved LV ejection fraction (LVEF). A total of 203 subjects suspected with coronary artery disease underwent chest radiography and dual source computed tomography coronary angiography (DSCT-CA). The LV systolic function parameters: LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), and LVEF were measured from the DSCT-CA. The association between CTR and LV systolic function parameters was analyzed according to LVEF value (<55%, depressed LVEF group; versus ≥55%, preserved LVEF group) and CTR value (<0.5, normal range CTR group; versus ≥0.5, larger CTR group). The LVEDVI and LVESVI were higher in the depressed LVEF group compared with the preserved LVEF group (108.56±57.15 vs. 67.52±14.56 ml/m2, P<0.001; and 64.07±37.81 vs. 20.23±7.23 ml/m2, P<0.001, respectively) and lower in the normal range CTR group compared with the larger CTR group (67.10±15.00 vs. 77.30±34.32 ml/m2, P=0.009 and 21.94±8.96 vs. 28.97±26.54 ml/m2, P=0.017, respectively). Significant correlations were found between CTR and LVEDVI, and LVESVI and LVEF in the depressed LVEF group (r=0.66, P<0.001; r=0.65, P<0.001; and r=−0.46, P=0.018, respectively). However, there was no significant association detected between CTR and LV systolic function parameters in the other subgroups. The LVEDVI and LVESVI showed an inverse correlation with the LVEF in each group. Although the CTR was not a reliable indicator of LV size and systolic function in patients with preserved LVEF, it was correlated with LV size and LVEF in patients with depressed LVEF.
PMCID: PMC4217771  PMID: 25371728
dual source computed tomography; chest radiography; cardiothoracic ratio; left ventricular systolic function; left ventricular volume index
18.  Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase 
Journal of medicinal chemistry  2013;56(19):10.1021/jm401037h.
High levels of striatal-enriched protein tyrosine phosphatase (STEP) activity are observed in a number of neuropsychiatric disorders such as Alzheimer’s disease. Over-expression of STEP results in the dephosphorylation and inactivation of many key neuronal signaling molecules, including ionotropic glutamate receptors. Moreover, genetically reducing STEP levels in AD mouse models significantly reversed cognitive deficits and decreased glutamate receptor internalization. These results support STEP as a potential target for drug discovery for the treatment of Alzheimer’s disease. Herein, a substrate-based approach for the discovery and optimization of fragments called substrate activity screening (SAS) has been applied to the development of low molecular weight (<450 Da) and non-peptidic, single-digit micromolar mechanism-based STEP inhibitors with greater than 20-fold selectivity across multiple tyrosine and dual specificity phosphatases. Significant levels of STEP inhibition in rat cortical neurons are also observed.
PMCID: PMC3875168  PMID: 24083656
19.  Multivariate Dimensionality Reduction Approaches to Identify Gene-Gene and Gene-Environment Interactions Underlying Multiple Complex Traits 
PLoS ONE  2014;9(9):e108103.
The elusive but ubiquitous multifactor interactions represent a stumbling block that urgently needs to be removed in searching for determinants involved in human complex diseases. The dimensionality reduction approaches are a promising tool for this task. Many complex diseases exhibit composite syndromes required to be measured in a cluster of clinical traits with varying correlations and/or are inherently longitudinal in nature (changing over time and measured dynamically at multiple time points). A multivariate approach for detecting interactions is thus greatly needed on the purposes of handling a multifaceted phenotype and longitudinal data, as well as improving statistical power for multiple significance testing via a two-stage testing procedure that involves a multivariate analysis for grouped phenotypes followed by univariate analysis for the phenotypes in the significant group(s). In this article, we propose a multivariate extension of generalized multifactor dimensionality reduction (GMDR) based on multivariate generalized linear, multivariate quasi-likelihood and generalized estimating equations models. Simulations and real data analysis for the cohort from the Study of Addiction: Genetics and Environment are performed to investigate the properties and performance of the proposed method, as compared with the univariate method. The results suggest that the proposed multivariate GMDR substantially boosts statistical power.
PMCID: PMC4178067  PMID: 25259584
20.  Feasibility of fine-needle aspiration biopsy and its applications in superficial cervical lesion biopsies 
The aim of the study was to investigate the feasibility and value of clinical application of fine-needle aspiration histological biopsy via ultrasound-guided thyroid nodule and enlarged cervical lymph node fine-needle aspiration histological biopsy. Fine-needle aspiration cytological and histological biopsies and surgical treatments were performed on 982 patients with thyroid nodule and 1435 patients with enlarged cervical lymph nodes. A comparative study of the histological and cytological examination results and post-surgical etiology results was subsequently conducted. Among the 982 thyroid nodule patients, the acquisition rates were 89.8% (882/982) for fine-needle aspiration histological biopsy and 96.2% (945/982) for cytological biopsy, while among the 1435 patients with enlarged cervical lymph nodes, the acquisition rate for fine-needle aspiration cytological biopsy was slightly higher than that for histological biopsy, with values of 95.7% (1374/1435) and 91.4% (1312/1435), respectively. For the thyroid nodule patients, when the acquired histological and cytological biopsy results were compared with the post-surgical etiology results, the sensitivity, specificity, and accuracy of the histological results were 98.5%, 100%, and 98.9%, respectively, whereas those of the cytological results were 86.8%, 82.9%, and 85.6%, respectively; the differences between the 2 biopsy methods were statistically significant (P < 0.05). For the patients with enlarged cervical lymph nodes, when the acquired histological and cytological biopsy results were compared with the post-surgical etiology results, the sensitivity, specificity, and accuracy of the histological results were 96.3%, 99.8%, and 97.6%, respectively, whereas the those of the cytological results were 76.8%, 92.1%, and 82.2%, respectively; again, the differences between the 2 methods were statistically significant (P < 0.05). In conclusion, Fine-needle aspiration histological biopsy is a reliable and highly accurate examination method. It is simple and feasible, thus facilitating the discrimination of malignant and benign thyroid nodules and enlarged cervical lymph nodes and playing an important role in the establishment of reasonable clinical therapeutic regimens.
PMCID: PMC4152081  PMID: 25197391
Thyroid nodule; cervical lymph node; fine-needle aspiration histology; fine-needle aspiration cytology
21.  Multi-Walled Carbon Nanotubes Impair Kv4.2/4.3 Channel Activities, Delay Membrane Repolarization and Induce Bradyarrhythmias in the Rat 
PLoS ONE  2014;9(7):e101545.
The potential hazardous effects of multi-walled carbon nanotubes (MWCNTs) on cardiac electrophysiology are seldom evaluated. This study aimed to investigate the impacts of MWCNTs on the Kv4/Ito channel, action potential and heart rhythm and the underlying mechanisms.
HEK293 cells were engineered to express Kv4.2 or Kv4.3 with or without KChIP2 expression. A series of approaches were introduced to analyze the effects of MWCNTs on Kv4/Ito channel kinetics, current densities, expression and trafficking. Transmission electron microscopy was performed to observe the internalization of MWCNTs in HEK293 cells and rat cardiomyocytes. Current clamp was employed to record the action potentials of isolated rat cardiomyocytes. Surface ECG and epicardial monophasic action potentials were recorded to monitor heart rhythm in rats in vivo. Vagal nerve discharge monitoring and H&E staining were also performed.
Induction of MWCNTs into the cytosole through pipette solution soon accelerated the decay of IKv4 in HEK293 cells expressing Kv4.2/4.3 and KChIP2, and promoted the recovery from inactivation when Kv4.2 or Kv4.3 was expressed alone. Longer exposure (6 h) to MWCNTs decreased the IKv4.2 density, Kv4.2/Kv4.3 (but not KChIP2) expression and trafficking towards the plasma membrane in HEK293 cells. In acutely isolated rat ventricular myocytes, pipette MWCNTs also quickly accelerated the decay of IKv4 and prolonged the action potential duration (APD). Intravenous infusion of MWCNTs (2 mg/rat) induced atrioventricular (AV) block and even cardiac asystole. No tachyarrhythmia was observed after MWCNTs administration. MWCNTs did not cause coronary clot but induced myocardial inflammation and increased vagus discharge.
MWCNTs suppress Kv4/Ito channel activities likely at the intracellular side of plasma membrane, delay membrane repolarization and induce bradyarrhythmia. The delayed repolarization, increased vagus output and focal myocardial inflammation may partially underlie the occurrence of bradyarrhythmias induced by MWCNTs. The study warns that MWCNTs are hazardous to cardiac electrophysiology.
PMCID: PMC4081717  PMID: 24992664
22.  Statistical Modeling Reveals the Effect of Absolute Humidity on Dengue in Singapore 
Weather factors are widely studied for their effects on indicating dengue incidence trends. However, these studies have been limited due to the complex epidemiology of dengue, which involves dynamic interplay of multiple factors such as herd immunity within a population, distinct serotypes of the virus, environmental factors and intervention programs. In this study, we investigate the impact of weather factors on dengue in Singapore, considering the disease epidemiology and profile of virus serotypes. A Poisson regression combined with Distributed Lag Non-linear Model (DLNM) was used to evaluate and compare the impact of weekly Absolute Humidity (AH) and other weather factors (mean temperature, minimum temperature, maximum temperature, rainfall, relative humidity and wind speed) on dengue incidence from 2001 to 2009. The same analysis was also performed on three sub-periods, defined by predominant circulating serotypes. The performance of DLNM regression models were then evaluated through the Akaike's Information Criterion. From the correlation and DLNM regression modeling analyses of the studied period, AH was found to be a better predictor for modeling dengue incidence than the other unique weather variables. Whilst mean temperature (MeanT) also showed significant correlation with dengue incidence, the relationship between AH or MeanT and dengue incidence, however, varied in the three sub-periods. Our results showed that AH had a more stable impact on dengue incidence than temperature when virological factors were taken into consideration. AH appeared to be the most consistent factor in modeling dengue incidence in Singapore. Considering the changes in dominant serotypes, the improvements in vector control programs and the inconsistent weather patterns observed in the sub-periods, the impact of weather on dengue is modulated by these other factors. Future studies on the impact of climate change on dengue need to take all the other contributing factors into consideration in order to make meaningful public policy recommendations.
Author Summary
As dengue virus transmission is through a human-to-mosquito-to-human cycle, the influence of meteorological factors on dengue is likely to be associated with their impact on mosquito populations and behavior. Other than the influence of weather factors, the shift of dominant serotypes and pre-emptive measures taken against dengue vectors may possibly affect the dengue transmission trend. In this study, we investigate the impact of weather factors on dengue in tropical Singapore, taking into consideration the disease epidemiology and profile of virus serotypes. We found that absolute humidity, as a composite index of mean temperature and relative humidity, is a more stable and better predictor for modeling dengue incidence than the other unique weather variables when virological factors are taken into consideration. This research suggests that absolute humidity needs to be considered together with all the other contributing factors in order to make meaningful public policy recommendations for dengue control.
PMCID: PMC4006725  PMID: 24786517
24.  Relationship between P53 Status and Response to Chemotherapy in Patients with Gastric Cancer: A Meta-Analysis 
PLoS ONE  2014;9(4):e95371.
Previous studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with gastric cancer. We therefore performed a meta-analysis to expound the relationship between p53 status and response to chemotherapy.
Thirteen previously published eligible studies, including 564 cases, were identified and included in this meta-analysis. p53 positive status (high expression of p53 protein and/or a mutant p53 gene) was associated with improved response in gastric cancer patients who received chemotherapy (good response: risk ratio [RR]  = 0.704; 95% confidence intervals [CI]  = 0.550–0.903; P = 0.006). In further stratified analyses, association with a good response remained in the East Asian population (RR = 0.657; 95% CI = 0.488–0.884; P = 0.005), while in the European subgroup, patients with p53 positive status tended to have a good response to chemotherapy, although this did not reach statistical significance (RR = 0.828, 95% CI = 0.525–1.305; P = 0.417). As five studies used neoadjuvant chemotherapy (NCT) and one used neoadjuvant chemoradiotherapy (NCRT), we also analyzed these data, and found that p53 positive status was associated with a good response in gastric cancer patients who received chemotherapy-based neoadjuvant treatment (RR = 0.675, 95% CI = 0.463–0.985; P = 0.042).
This meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in gastric cancer. Further prospective studies with larger sample sizes and better study designs are required to confirm our findings.
PMCID: PMC3989310  PMID: 24740294
25.  Highly Selective Domino Multi-Cyclizations for Forming Polycyclic Fused Acridines and Azaheterocyclic Skeletons 
Organic letters  2013;15(7):1540-1543.
Highly selective four-component domino multi-cyclizations for the synthesis of new fused acridines and azaheterocyclic skeletons have been established by mixing common reactants in isobutyric acid under microwave irradiation. The reactions proceeded at fast rates, and were conducted to completion within 20–30 min. Up to seven new chemical bonds, four rings and four stereocenters were assembled in a convenient one-pot operation. The resulting hexacyclic and pentacyclic fused acridines and their stereochemistry have been fully characterized and determined by X-ray structural analysis.
PMCID: PMC3635953  PMID: 23506186

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